DE2429184A1 - PROCESS FOR THE SELECTIVE CLEAVAGE OF THE AMIDIC ACID GROUP OF A 7- (AMIDIC ACID) CEPHALOSPORIN OR 6- (AMIDIC ACID) -PENICILLIN AND SUITABLE COMPOUNDS - Google Patents

Description

PATENT LAWYERS

DR. I. MAAS

DR. G. SPOTT

BCCO MONCHSN 40

SCHLEiSSHEiMERSTR. 299

TEL. 3592201/205

Eli Liily and Company, Indianapolis, Indiana, V.St.A, Process for the selective cleavage of the amic acid group

of a 7- (amic acid) cephalosporin or 6- (amic acid) - penicillins and compounds suitable therefor

The invention relates to a method for selective cleavage the amic acid group of a 7- (amic acid) cephalosporin or 6- (amic acid) penicillins by elimination of water with formation the corresponding new 7-isoimidocephalosporin or δ-isoimidopenicillin compounds. The 7-isoimidocephalosporin obtained in this way or 6-isoimidopenicillin is formed to form the corresponding 7-aminocephalosporin or 6-aminopenicillin or the corresponding 7-acylamidocephalosporin or 6-acylamidopenicillins are further cleaved.

In the development of cephalosporin antibiotics it has been common practice for some time to have an imide substituent in the 7 or 6 position to be used if this part of the molecule is not at the core of the relevant research work. Through the present such a protective group, especially the phthalimido group,

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this position becomes quite chemically inert, which leads to Let other parts of the molecule be treated relatively carelessly and at the same time be relatively safe can that this position remains intact,

It has long been known, however, that an imide function is in position 7 of a cephalosporin or in position 6 of a penicillin makes the structure only minimally antibiotic. Unfortunately, a 7-imido group has not yet been successfully released from a cephalosporin or penicillin cleave the protected amino group. Research must therefore deal with a stable substituent in this position and thus a group that gives a cephalosporin or penicillin only minimal antibiotic effects. The usage such a substituent is therefore economical interesting only if it can be readily removed at any desired point in a synthetic process.

However, the foregoing is not intended to generally mean that successful cleavage of an imide group is impossible. There are already several procedures for such a split. So be in Japanese Publication by Minoru Shindo, "Cleavage Reactions of the Phthalimide Group ", Yuki Gosei Kagaku Kyokai Shi, 29 (5), (1971) pages 496-509, a series of cleavage techniques discussed. Each of these working methods can be used to split the imide function of a cephalosporin or penicillin, if that were the only major consideration. However, it is at least as important to work under conditions through which a cleavage can be achieved without affecting the structure of the cephalosporin or penicillin molecule is attacked or destroyed. The latter, however, has not yet been achieved.

40 98 8J / 1243

A partial cleavage of the imide side chain of a cephalosporin or A penicillin structure with the formation of the corresponding amic acid side chain was already possible (see, for example, Sheehan et al., Journal of the America Chemical Society, 73, (1951) Pages 4367-4372; Sheehan et al., Journal of the American Chemical Society, 78, (1956) pp. 3680-3683; Perron et al., Journal of Organic Chemistry, 7 (1964) pp. 483-487). the Phthalimide was made through alkaline hydrolysis like them for example, described in Sheehan's first publication is converted into the corresponding phthalamic acid. However, as from the second publication by Sheehan shows, all attempts at further cleavage were unsuccessful because the ß-lactam ring of penicillin is preferably opened with destruction of the penicillin.

US Pat. No. 3,487,074 discloses the cleavage of 6-phthalimido-3-penamylcarboxylic acid described by treatment with hydrazine hydrate in dioxane at room temperature for 12 hours. This method however, does not work on penicillins and cephalosporins. A certain success was achieved with the

2
Achieve cleavage of a 7-phthalimido-delta-cephalosporin / see Spry, D. Ο., Journal of the American Chemical Society, 92, (1970), p. 5007 /.

. A 0 9 0 8 1 / V2 4 3

The invention is also directed to new intermediates, which are suitable for the cleavage of the amic acid function, as well as at separate conversion stages in the entire cleavage process.

The invention accordingly relates to a process for cleaving the amic acid function of a compound of the formula

R -C-C-N

COORi

wherein R and R stand for hydrogen or R and R together a a

one with the carbon atoms to which they are attached ortho-phenylene ring mean the substituent Z for

or

stands,

R _{1 is} hydrogen or a carboxy protecting group and

R _{2 represents} hydrogen, acetoxy, methoxy, methylthio, (5-methyl-1,3,4-thiadiazol-2-yl) thio or (1-methyl-iH-tetrazol-5-yl) thio,

characterized in that one

(1) from the above compound to form the corresponding isoimide of the formula

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O = C

Splits off water.

COOR,

this Isoiiaid with a hydrazine of the formula

R ₃ HNIiHR ₄ ,

wherein R ₃ and R. independently of one another represent hydrogen or methyl, reacts, and

(3) a) the reaction mixture obtained in this hydrazine treatment with an acyl halide to form the corresponding T-acylamidocephalosporins or e-acylamidopenicillins or

b) the corresponding 7-aminocephalosporin or 6-aminopenicillin, if at least one of the substituents R ₃ or R _{4 is} methyl, is obtained from the reaction mixture of the above hydrazine treatment, or

c) the Reaktionsgeiaisch from the above hydrazine, if the substituents R, and R. are hydrogen, heated to a temperature of about 50 to about 100 ⁰ C and thus obtains the corresponding 7-amino cephalosporin or 6-aminopenicillin or

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d) the reaction mixture from the above hydrazine _{treatment, if the substituents R 3} and R _{4 are} hydrogen, treated with an acid and thus obtained the corresponding 7-aminocephalosporin or 6-aminopenicillin in the form of their acid addition salts.

The invention also relates to a process for making an isoimide of the formula

= C

O = C

_N

COOR

directed, which consists in the fact that one is made of an aeroic acid the formula

R -CC-NH
a ">>

R-C

COOH 0 "

COOR ₁

where the substituents R, R, Z and R _{1 of} the above formulas

el I

have the meanings already given, splitting off water.

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The invention also relates to a method for cleavage the isoimido function of an isoimide compound of the formula

COOR1

wherein R, R, Z and R _{1 have} the meanings already mentioned a ι

have by getting

(1) this isoimide compound with a hydrazine of the formula

R ₃ HNNHR ₄

converts, wherein R ₃ and R. are independently hydrogen or methyl, and

(2) a) the reaction mixture obtained in this hydrazine treatment with formation of the corresponding 7-acylamidocephalosporin or 6-acylamidopenicillin is reacted with an acyl halide or

b) if the substituents R ₃ and R _{4 are} methyl, the corresponding 7-aminocephalosporin or 6-aminopenicillin is obtained from the reaction mixture of the above hydrazine treatment or

c) if the substituents R ₃ and R _{4 are} hydrogen, the reaction mixture of the above hydrazine treatment to form the corresponding 7-aminocephalosporin or. 6-aminopetiicillins heated to a temperature of about 50 to about 100 ⁰ C, or

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d) if the substituents R ₃ and R _{4 are} hydrogen, the reaction mixture obtained from the above hydrazine treatment is treated with acid to form the acid addition salts of the corresponding 7-aminocephalosporin or 6-aminopenicillin.

Finally, the invention is based on valuable intermediates directed for the method according to the invention, which has the formula

R R

COOR1

have, in which R, R, Z and R _{1 have} the abovementioned meanings

a ι

have genes.

Unless otherwise specifically stated, cleavage means the removal of a substituent in position 7 Cephalosporins or in position 6 of a penicillin with the formation of a free 7-aminocephalosporin or 6-aminopenicillin, corresponding acid addition salts of such compounds or by removing the 7- or 6-substituent and subsequent reacylation with the introduction of another acyl substituent in position 7 or position 6 Connections understood.

The first stage of the process according to the invention consists in splitting off water from the amic acid function Formation of the corresponding isoimide. If with this AIDS acid structure the substituents R and R together with the

el

Carbon atoms to which they are attached, an ortho-phenylene ring mean then is the source of the amic acid

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generally a phthalimido compound / which is known in Way was partially split. The structure of this obtained phthalemic acid is as follows:

COORi

The preparation of a compound of the above structure from the corresponding phthalimido compound is known, and it can be carried out under all known conditions. A typical process leading to a partial split leads, consists in an alkaline hydrolysis, as it is for example by Sheehan et al. in Journal of the American Chemical Society, 73, (1951) pages 4357-4372 is.

For an alkaline hydrolysis that leads to partial cleavage the amic acid is suitable, an alkali metal hydroxide is used, for example or sulfide, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium sulfide, potassium sulfide or lithium sulfide. Generally from about 1 to about 2 equivalents of alkali hydroxide or sulfide are used, with the exception of the Case in which the free acid of the cephalosporin or penicillin is assumed, since here the free carboxyl group. itself consumes one equivalent of the alkali reagent, so that another equivalent thereof is required. The pH value of the reaction medium is generally between about 9 and about 11. This can usually be achieved by using an aqueous medium which is inert and miscible with water contains organic solvent, such as

0 9 8 8 1/12 4

- 1G -

Tetrahydrofuran, Ν, Ν-dimethylformamide, acetone, diethylsulfoxide or dioxane.

The partial cleavage is generally fairly rapid and is usually complete within about 3 to about 30 minutes, and especially within about 5 to about 10 minutes. The reaction temperature is usually about -10 C to about room temperature, and it is preferably about 0 ⁰ C.

The amic acid can also have the formula

I!

HC-C-NH

I. Υ—
HC

/ Y N

COORt

to have. This amic acid and the above-mentioned phthalamic acid are also available from sources other than the corresponding imide precursors. For example, you can use the free amino compound with the corresponding anhydride, for example maleic anhydride, to form the corresponding Treat the amic acid compound, in this case in particular to form the 3-carboxyacrylamido compound.

The dehydration step in the process according to the invention consists in converting the amic acid to an isoimide. The isoimides formed are new compounds and as such are also part of the subject matter of the invention. You have the formula

0 9 8 6 1/12 4

R. Ra

ι ι

C = C

COORi

Various methods are available for converting the amic acid to the isoimide. With e; Lnem of these procedures a dehydrating agent used, such as N, N '~ dicyclohexylcarbodiimide (DCC), N-ethoxycarbonyl-2-ethoxy-i, 3-dihydroquinoline (EEDQ), 1-cyclohexyl-3- (2-morholinoethyl) carbodiimide metho-p-toluenesulfonate, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride or N-trifluoroacetylimidazole. For the sake of simplicity, DCC is preferably used. In one suitable solvents are in particular e: in equivalents DCC and 1 equivalent of the amic acid mixed together. You can also use an excess of DCC. However, it is best to work with an amic acid based on the amount related equivalent amount, as there is an excess DCC is generally difficult to remove from the product. Naturally you can also use a smaller amount of DCC compared to the amic acid. However, this leads to an undesirable incomplete conversion of the amic acid. In general, therefore, equivalent amounts of amic acid and DCC are used together in a suitable solvent, in particular an aprotic solvent, namely a solvent that neither delivers protons nor is a proton acceptor, mixed with one another. A number of these are known to those skilled in the art Known solvents, and these can all be used in the process according to the invention. To such solvents include, for example, N, N'-dimethylformamide, N, N'-dimethylacetamide, Tetrahydrofuran, dioxane, aliphatic nitriles, such as

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Acetonitrile or propionitrile, aromatic hydrocarbons and their halogen derivatives, such as benzene, toluene or dichlorobenzene, as well as aliphatic halogenated hydrocarbons, such as methylene chloride, chloroform, bronioform, carbon tetrachloride, Carbon tetrabromide, ethylene dichloride or ethylene dibromide.

The DCC and the amic acid is allowed in the inert medium at a temperature of about 0 ⁰ C to about 30 ⁰ C for a period of about 15 minutes to about 2 hours, and preferably, react for about one hour each other. The isoimide thus obtained is isolated from the reaction mixture in a known manner.

Another method of converting the amic acid into a Isoimide consists in the reaction of the amic acid with trifluoroacetic anhydride in the presence of a tertiary amine.

The reaction is typically carried out in an aprotic solvent of the type mentioned above. For this mixing a tertiary amine, for example N-methylmorpholine, Triethylamine, pyridine, quinoline or N, N "-Dimethy1-aniline, in an amount of about 1 to about 2 moles per mole of the amic acid with the amic acid in the aprotic solvent, and then added to this mixture, based on the amic acid, with a molar equivalent or a slight excess Trifluoroacetic anhydride. If the reaction medium is practically anhydrous, then a moderate excess of trifluoroacetic anhydride can be used use. If there are substantial amounts of water in the reaction medium, then the trifluoroacetic anhydride is thereby decomposed with the formation of trifluoroacetic acid, which is because of the protic The nature of this acid adversely affects the implementation.

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The reaction is carried out at temperatures between about 0 ° C. and about 30 ° C. and is generally within finished about 15 minutes to about an hour.

Another process for the conversion of amic acid into the isoimide consists in a reaction of amic acid with an alkyl chloroformate, for example ethyl chloroformate, propyl chloroformate _r t-butyl chloroformate or isobutyl chloroformate. However, the conversion to the isoimide using an alkylchlorine ormiats has the disadvantage that the substituent R _{1 of} the amic acid compound cannot stand for hydrogen. One must therefore start from a carboxy-protected compound. The chloroformate reaction is carried out in the presence of a tertiary amine, for example pyridine, quinoline, triethylamine, N-methylmorpholine or N, N-dimethylaniline. As with the conversions already mentioned, this conversion is typically also carried out in the presence of an aprotic organic solvent of the type mentioned above. Based on the amic acid, at most one equivalent of the amine is used, and in particular a slight deficit of amine is used. Any excess of tertiary amine tends to convert the amic acid into an imide, regardless of which original starting material is used for the process according to the invention. A slight excess of chloroformate can be used. However, this is not preferred, since any excess thereof present in the product reacts with the hydrazine used in the subsequent next stage of the process according to the invention.

The reaction is over a period of about 5 to about 40 minutes, preferably from about 20 to about 30 minutes, at a temperature of about -20 ⁰ C to about +5 ⁰ C, preferably from about -20 ⁰ C to about -5 ⁰ C, performed. The isoimide is obtained by adding the reaction mixture after completion

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The reaction was warmed to room temperature and the desired product was isolated in a known manner.

The above-mentioned isoimide cephalosporins or penicillins can be broken down by stepwise treatment with hydrazine, in particular unsubstituted hydrazine, methylhydrazine or Ν, Ν'-dimethylhydrazine, treated and the desired product then continues to gain and / or depending on the actual product desired and the particular hydrazine used treated.

The hydrazine treatment consists in reacting the isoimide in an inert organic solvent, for example an aprotic solvent of the type mentioned above, with one equivalent of the hydrazine. An excess of hydrazine must be avoided. To ensure this, up to one equivalent of hydrazine is used per equivalent Isoimide, and especially a slight excess of hydrazine. The implementation takes place at relatively low temperatures carried out, for example at temperatures between about -76 C and room temperature, and preferably at about ice temperature (0 C) or below. The hydrazine becomes the isoimide mixture best added while this mixture is at a relatively low temperature. The mixture of Isoimides in the organic solvent are therefore kept at the reaction temperature while the pre-cooled one Adds hydrazine. Implementation is pretty quick. It is generally completed within about 1 to 10 minutes, whereupon the reaction is normally allowed to continue for about 5 minutes.

The particular treatment that the hydrazine reaction mixture then receives depends on the structure of the hydrazine used and the desired end product.

4 0 9 8 8 1/12 4 3

The hydrazines used have the structure

R ₃ IlNNHR ₄ ,

wherein R_ and R. independently of one another are hydrogen or methyl. If one or both substituents R una Π. Mean methyl then is no further treatment more is required, since one then, to the free 7-aminocephalosporin or 6-aminopenicillin, which can easily be isolated in a known manner.

If the substituents R ₃ and R in the hydrazine used both mean hydrogen, then a complex is formed from the free 7-Z \ minocephalosporiri or 6-aminopenicillin and the grape product, namely diketophthalazine, and this complex must be destroyed. This can be accomplished by heating the reaction mixture, treating it with an acid, or more easily, a combination of both treatments.

To destroy the complex by applying heat, it is best to bring the reaction mixture to a temperature of about 50 to about 100 ° C over a period of about 5 to about 20 minutes, where:
wins in a known way.

about 50 to about 100 C, whereupon the free amino compound

However, as already mentioned, the diketophthalazine complex can also be destroyed by treating the reaction mixture with an acid. Any organic or inorganic acid can actually be used for this purpose. Typical acids of this type are, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, p-toluenesulfonic acid, sulfuric acid or methanesulfonic acid. For this purpose, based on the isoimide, it is expedient to use an equivalent or a moderate excess of acid , in particular up to about 2 equivalents of acid being used. The use of acid is preferred

40988Ί / 12 43

in connection with heating, and the reaction mixture obtained is therefore ^{heated to temperatures between about 50 and about 100 °} C., and the decomposition of the complex is then allowed to proceed. Depending on the respective temperature; the reaction is typically complete within about 5 to about 10 minutes. When using an acid, acid salts of the free aminocephalosporin or penicillin are formed. These products can be obtained in a known manner.

A 7-acylamidocephalosporin or a 6-acylamidopenicillin can also be prepared by using the hydrazine reaction mixture treated with an acyl halide containing an acyl function, which in combination with the 7-aminocephalosporin or 6-aminopenicillin to the desired Acylamido function arrives. By using an acyl halide eliminates the need for heating or acid treatment to decompose the diketophthalazine complex Avoid, if this has occurred, since the acyl halide itself is sufficiently acidic for the necessary decomposition is. In this way, in position 7 of the cephalosporin molecule or in position 6 of the penicillin molecule by simply selecting the particular acyl halide, preferably of the corresponding acyl chloride, introduce all desired acyl functions. The acylamidocephalosporin obtained or penicillin can then be obtained in a known manner.

Typical acyl halides used in the preparation of the Finally, the desired acylamido product can be used, are those of the formula

wherein Y is halogen, such as chlorine, bromine or iodine, and

409881/1243

R _x for

-Cg-alkanoyl,

C ₀ -C ₀ -ChIOr- or Brömalkanoyl, Azidoacetyl, Cyanoacetyl, 2-Sydnon-3-C ..- C ^ -alkanoyl,

N = GH
¹ > N-fCH J- C (O) -,

where m is 0, 1 or 2,

Q
Ar-CC (0) -,

in which Q is in each case hydrogen or methyl and Ar is 2-thieriyl, 3-thienyl _f 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, phenyl or by chlorine, bromine, iodine, fluorine, tri-fluoromethyl, hydroxy , C ₁ -C ₃ -A ^ yI, C ₁ -C ₃ -AIkOXy, cyano or nitro-substituted phenyl,

Ar-X-CH ₂ -C (O) -,

wherein X is oxygen or sulfur and Ar is the above Has meaning, or is 4-pyridyl, where X then Sulfur means, or

409881/1243

Ar-CH ₀ -C (O) -,
B.

stands,

wherein Ar has the above meaning and B for amino, through benzyloxycarbonyl, C.-C.-alkoxycarbonyl, cyclopentaloxy carbonyl, cyclohexyloxycarbonyl, benzhydryloxycarbonyl, tripheny! methyl, 2,2,2-trichloroethoxycarbonyl,

-C (O) NH-C-NH ₀

Il ~

NH. or the enamine of methyl acetoacetate or acetylacetone protected amino, hydroxy or by esterification with a C ₁ -Cg alkanoic acid protected hydroxy, carboxy or by esterification with a C. -Cg alkanol protected carboxy, -N ₃ , -CN or -C ( O) NH ₃ stands.

As a starting material for the process according to the invention Cephalosporin or penicillin used has the following formula:

O
! I

R -CC-NH _x

RC
I.

COOH 0

COOR1

The substituent R .. means in this formula as well as in the various products of the process according to the invention hydrogen or a carboxy protective group. The type of Carboxy protecting group is not important and it can be any known protecting group. Preferably However, this group is the remainder of an ester function, which can be obtained by acid treatment or by

409881/1243

Can split off hydrogenation. Preferred carboxy protective groups include, for example, Cj - ^ - alkyl, 2,2,2-trihaloethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, C ^ Cg-alkanoyloxyinethyl, phenacyl or p-halophenacyl, with halogen in each case being chlorine and bromine or iodine. Typical examples of the preferred ester residues of the carboxyl group of the imidocephalosporin or penicilli compounds which are used according to the invention include, for example, methyl, ethyl, n-propyl, isopropyl, η-butyl, sec-butyl, isobutyl, t-butyl, 2,2 , 2-Trichloräthy1, 2,2 , 2-Tribromäthy1, p-nitrobenzyl, benzyl, p-methoxybenzyl, benzhydryl, acetoxymethyl, pivaloyloxymethyl, propionoxymethyl, phenacyl, p-chlorophenacyl or p-bromophenacyl.

The total ester residues are t-butyl, benzyl and p-nitrobenzyl , p-methoxybenzyl, benzhydryl and 2,2,2-trichloroethy1 preferred.

As already mentioned above, the substituent R ₁ in the above formula can also be hydrogen in addition to a carboxy protective group. Accordingly, either the free cephalosporic acid or the free penicillic acid can be used for the process according to the invention.

The substituent R ₁ stands in particular for hydrogen or p-nitrobenzyl.

The 7 position of the cephalosporin or the 6 position of the penicillin contain a 2-carboxybenzamido group in the above formula (which is derived in particular from a phthalimido group) or a maleamido group.

9: 801/1243

- 2ο -

The method according to the invention therefore runs in stages from a (2-carboxybenzamido) - via a phthalisoimido to an amino or acylamido cephalosporin or penicillin.

The inventive method can also be with a Maleamidocephalosporin or penicillin begin .. This gradual sequence of reactions involves a conversion of a Maleamiüocephalosporins or penicillins via a Maleisoimidocephalosporin or penicillin to an amino or acylamido cephalosporin or penicillin.

The following groups can be found in position 3 of the 7- (amic acid) cephalosporin used as the starting product: methyl _r acetoxymethyl, llethoxymethyl, methylthiomethyl, (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl or (1- Methyl-1H-tetrazol-5-yl) thiomethyl. The substituent present in position 3 of the cephalosporin starting material remains intact throughout the entire reaction sequence according to the invention.

Typical product conversions which can be carried out according to the invention are given below. The relationship of course, the individual products will vary depending on the reactants used, the proportions of these reactants and the reaction conditions.

Methyl 7- (2-carboxybenzamido) -3-methyl-3-cephem-4-carboxylate to methyl 7-phthalisoimido-3-methyl-3-cephem-4-carboxylate 'to the methyl 7-amino-3-methyl-3-cephem-4-carboxylate.

2,2 ^ -Trichloroethyl -? - (2-carboxybenzamido) -3-acetoxymethyl-3-cephem-4-carboxylate to 2,2,2-trichloroethyl-7-phthalisoimido-3-acetoxymethyl-3-cephem-4-carboxylate to 2,2,2-trichloroethyl ^ -amino-S-acetoxymethyl-S-cephem ^ -carboxylate.

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p-Nitrobenzyl 7- (2-carboxybenzamido) -3-methoxymethyl-3 * -cephem-4-carboxylate to p-nitrobenzyl-7-phthalisoimido-3-methoxymethyl-3-cephem-4-carboxylate to p-nitrobenzyl-7-amino-3-methoxymethyl-3-cephem-4-carboxylate.

Benzyl 7- (2-carboxybenzamido) - ^ - methylthiomethyl ^ -cephem-4-carboxylate to benzyl ^ -phthalisoimido-S-methylthiomethyl-3-cephem-4-carboxylate to benzyl 7-amino-3-methylthiomethyl-3-cephem-4-carboxylate.

Benzhydry 1-7- (2-carboxybenzamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylate to benzhydryl 7-phthalisoimido-3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylate to benzhydryl 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate.

t -Butyl 7- (2-carboxybenzamido) -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylate to t-butyl-7-phthalisoimido-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate to t-butyl 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate.

p-Nitrobenzyl 7- (2-carboxybenzamido) -3-acetoxymethyl 1-3-cephem-4-carboxylate to p-nitrobenzyl ^ -phthalisoimido-S-acetoxymethyl-3-cephem-4-carboxylate to p-nitrobenzyl-7-amino-3-acetoxymethyl-3-cephem-4-carboxylate.

p-Nitrobenzyl 7- (2-carboxybenzamido) -3-methyl 1-3-cephem-4-carboxylate to p-nitrobenzyl-7-phthalisoimido-3-methyl-3-cephem-4-carboxylate to p-nitrobenzyl-7-amino-3-methyl-3-cephem-4-carboxylate.

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p-Nitrobenzyl 7- (2-carboxybenzamido) -3-methylthiomethyl-3-cephem-4-carboxylate to p-nitrobenzyl-7-phthalisoimido-3-methylthiomethyl-3-cephem-4-carboxylate to p-nitrobenzyl-7-amino-3-methylthiomethyl-3-cephem-4-carboxylate.

p -Nifcrobenzyl 7- (2-carboxybenzamido) -3- (5-methy1-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate to p-nitrobenzyl ^ -phthalisoimido-S- (5-mefchyl-1 , 3, 4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate to p-nitrobenzyl-7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate.

p-Nitrobenzyl 7- (2-carboxybenzamido) -3- (1-methyl-iH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate to p-nitrobenzyl-7-phthalisoimido-3- (1-methyl-iH-tetrazol-5-yl) thiomethyl-3-cephera-4-carboxylate to p-nitrobenzyl-7-amino-3- (1-methyl-iH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate.

p-Methoxybenzyl 7- (2-carboxybenzamido) -3-acetoxymethyl-3-cephem-4-carboxylate to p-methoxybenzyl-7-phthalisoimido-3-acetoxymethyl-3-cephem-4-carboxylate to p-methoxybenzyl-7-amino-3-acetoxymethyl-3-cephem-4-carboxylate.

p -Nifcrobenzyl-7-maleamido-3-methyl-3-cephem-4-carboxylate to p-nitrobenzyl-7-maleisoimido-3-methyl-3-cephem-4-carboxylate to p-nitrobenzyl ^ -amino-S-methyl ^ -cephem ^ -carboxylate.

2, 2, 2-trichloroethyl-7-malearnido-3- (1-methyl-iH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate to 2, 2.2, -Trichloräthyl ^ -maleisoimido-S - (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate for the 2,2, 2-trichloroethyl 7-amino-3- (1-methyl-1H-tetrazol-5-yl ) thiomethyl 3-cephem-4-carboxylate.

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Benzyl T-maleamido ^ - (5-methyl-1, 3, 4-thiadiazol-2-yl) thiomethyr-3-cephem-4-carboxylate to benzyl-7-maleisoimido-3- (5-methyl-1 , 3, 4-thiadiazol-2-yl) thiol-3-cephem-4-carboxylate to benzyl-V-amino-S- (5-methyl-1, '3, 4-thiadiazol-2-yl) th i onie thy 1 - 3 - cepheni- 4 - c a r b oxy 1 at.

Pivaloyloxyinethyl 7- (2-carboxybenzamido) -3-methylthiomethyl-3-cephem-4-carboxylate to pivaloyloxymethyl-7-phthalisoimido-3-methylthioraethyl-3-cephem-4-carboxylate to pivaloyloxymethyl-7 ^ amino-3-methylthiomethyl 1-3-cephem-4-carboxylate.

J \ cetoxymethyl 7- (2-carboxybenzamido) -S-raethoxymethyl-S-cephem-4-carboxylate Do acetoxymethyl 7-phthalisoimido-3-methoxymethyl-3-cephem-4-carboxylate to acetoxymethyl-7-amino-3-methoxymethyl-3-gephem-4-carboxylate.

Phenacyl 7- (2-carboxybenzamido) -3-methy 1-3-cephem-4-carboxylate to phenacyl-7-phthalisoiniido-3-jaethy 1-3-cephem-4-carboxylate to .Phenacyl ^ -amino-S-methyl - ^ - cephem ^ -carboxylate.

p-Chlorophenacyl-7- (2-carboxybenzamido) -S-cephein-4-carboxy! at to p-chlorophenacyl-7-phthalisoimido-S-acetoxymethyl-S-cephem-4-carboxylate to p-chlorophenacyl-7-amino-3-acetoxymethyl-3-cephem-4-carboxylate. ·

7- (2-Carboxybenzamido) -3-methyl-3-cephem-4-carboxylic acid for 7-PhthalisOimido ^ -methyi-S-cephem-4-carboxylic acid to form 7-amino-3-methyl-3-cephem-4-carboxylic acid.

7- (2-Carboxybenzamido) ^ -aeetoxymethyl-S-cephem ^ -carboxylic acid to 7-phthalisoimido-3-acetoxymethyl-3-cephem-4-carboxylic acid to 7- / jnino-3-acetoxymethyl-3-cephem-4-carboxylic acid.

81/12 4 3

7- (2-Carboxybenzamido) -S-methoxymethyl-S-cephem-'l-carboxylic acid to 7-phthalisoimido-3-methoxγmethyl-3-cephem-4-carboxylic acid to 7-amino-3-methoxymethyl 1-3-cephem-4-carboxylic acid.

7- (2-Carboxybenzamido) -3-methylthiomethyl 1-3-cephem-4-carboxylic acid to 7-phthalisoimido-3-methylthioInethyl-3-cephem-4-carboxylic acid to 7-amino-3-methylthioInethyl-3-cephem-4-carboxylic acid.

7- (2-Carboxybenzamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid to the 7-phthalisoimido-3- (5-ynethyl-i , 3,4-thiadiazol-2-yl) thioiuethyl-3-cephem-4-carboxylic acid to 7-Ämiho-3- (5-methyl-1, 3, 4-thiadiazol-2-yl) thioinethyl-3-cephem-4-carboxylic acid.

7- (2-Carboxybenzamido) -3- (1-methyl-IH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid to phthalisoimido-3- (1-methyl-IH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid to 7-amino-3- (1-methyl-IH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid.

The end product in the above list is given in the form of the respective free 7-amino compound. At the In the process according to the invention, however, this end product is originally obtained in the form of an acid treatment of the respective acid addition salt. This salt can of course easily be converted into the free 7-amino compound in a known manner convert.

In addition, the above-mentioned procedural conversions no other aspect of the invention, namely the possibility, instead of the free 7-amino compound or the corresponding acid addition salt to a 7-acylamido compound to get. This product can be obtained by operating in the presence of an acid halide, namely

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in particular of the acid chloride, · that of the end product contains desired 7-acylamido function. The acyl halide is used instead of the acid in the final stage of the cleavage process. It was found that with this procedure the acid halide is itself sufficiently acidic to cause cleavage of any intermediate product contained in the Reaction mixture from the hydrazine treatment may be present. Simultaneously with this, the free 7-amino group then becomes acylated to the corresponding 7-acylamido compound.

By appropriate choice of the respective acyl halide introduce any known acyl group in position 7. Suitable Examples are phenyl, acetyl, phenoxyacetyl, phenylglycyl, 2-thienylacetyl or mandelyl.

Virtually any acyl halide can be used. Typical Acyl halides of this type are, for example, acetyl chloride, Hexanoyl bromide, chloroacetyl chloride, gamma-bromooctanoyl chloride, Azidoacetyl bromide, cyanoacetyl chloride, sydnonacetyl chloride, Tetrazole acetyl chloride, 2-thienylacetyl chloride, 3-thienylacetyl bromide, 2-furylacetyl iodide, 3-furylacetyl chloride, 2-Pyrrollacetylbromid, 3-Pyrrollacetylchlorid, Phenylacetyl chloride, alpha, alpha-dimethylphenylacetyl chloride, p-chlorophenylacetyl chloride, m-bromophenylacetyl bromide, p-iodophenylacetyl chloride, p-fluorophenylacetyl chloride, m-trifluoromethylphenylacetyl bromide, p-hydroxyphenylacetyl chloride, p-tolylacetyl bromide, m-methoxyphenylacetyl chloride, p-cyanophenylacetyl chloride, p-nitrophenylacetyl bromide, phenoxyacetyl chloride, Phenylthioacetyl chloride, p-hydroxyphenoxyacetyl bromide, 4-pyridylthioacetyl chloride, m-chlorophenoxyacetyl chloride, alpha-aminophenylacetyl chloride, N- (benzyloxycarbonyl) -alpha-aminophenylacetyl bromide, N- (methoxycarbonyl) -alpha-aminophenylacetyl chloride, N- (cyclopentyloxycarbonyl) -alpha-aminophenylacetyl chloride, N- (Cyclohexyloxycarbonyl) -alpha-aminophenylacetyl chloride, N- (Benzhydryloxycarbonyl) -alpha-aminophenylacetyl bromide,

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N- (triphenylmethyl) -alpha-aminophenylacetyl chloride, N- (2,2,2-trichloroethoxycarbonyl) -alpha-aminophenylacetyl chloride, alpha-hydroxyphenylacetyl chloride, alpha-formyloxyphenylacetyl chloride, alpha-acetoxyphenylacetyl chloride, alpha-carboxyphenylacetyl chloride, alpha-methoxycarbonylphenylacetyl chloride, alpha- (t-butoxycarbonyl) phenylacetyl chloride, alpha-azidophenylacetyl chloride, alpha-cyanophenylacetyl chloride or alpha-carbamoylphenylacetyl chloride.

Of course, any of the above-mentioned conversion sequences can be used also apply to the corresponding penicillin compounds substituted in position 6. The penicillin conversions are not intended to be limited to those penicillins that are detailed above in connection with the cephalosporins were mentioned. In general, any of the penicillins defined herein can be used. In the penicillin series there is of course not the group designated with R above, and in the List of the conversion sequences described above more typical Appropriate modifications are therefore required for cephalosporins.

The products produced by the process according to the invention and intermediates can be isolated in the usual way. This can be done, for example, by chromatography or filtration or recrystallization.

Is the end product of the process according to the invention Ester, then this product can be converted into an effective antibiotic by adding the ester function for the corresponding acylation of the free amino function in a known manner. The ester cleavage can by Treating the ester with an acid such as trifluoroacetic acid or hydrochloric acid, or with zinc and acid, such as formic acid, acetic acid or hydrochloric acid,

4 0 9 8 8 1/12 4 3

be made. It can also be hydrogenated of the ester in the presence of palladium, rhodium or a Compound thereof in suspension or on a carrier such as barium sulfate, charcoal or alumina.

The invention is illustrated in more detail by means of the following examples.

Method A. ? -Phthalmido-3-methyl-3-cephem-4-carboxylic acid

142 g of sodium bicarbonate are slowly added to a suspension of 181 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid (7-ADCA) in 1700 ml of water, after which a solution of 186 g of N-carbethoxyphthalimide in 1 liter of acetone are added, the solution is stirred for 3 hours, then cooled in an ice-water bath and acidified to pi: 2.1 by adding 600 ml of 42.5 percent phosphoric acid The precipitate is filtered off, washed with water and dried in vacuo to give 227 g of a mixture of the starting material and the desired phthalimido compound The mixture is separated by extraction with warm acetone and ethyl acetate to give 105 g of 7-ADCA of phthalimido compound is 1 1 4 g. A sample (1 g) of the product is recrystallized from acetone (15 ml). The resulting crystals melt at 223 to 225 ° C and have the following additional characteristics: / alpha / + 428.02 ° (MeC N); IR (Nujol) 1810, 1785, 1740 and 1710 cm "¹; NMR (CDCl ₃ ) delta 2.38 (s, 3, CH ₃ ), 3.0 and 3.75 (ABq, 2, J = 14 Hz) , 5.13 (d, 1, Jv = -4.5 Hz), 5.71 (d, 1, J = 4.5 Hz) and 7.82 (m, 4, ArII).

AO 9 8 8 1/12 43

Analysis for

Calculated: C, 55.81; H 3.51; N 8.14; O 23.23; S 9.31; Found: C, 55.72; H 3.38; N 8.17; O 23.51; S 9.27%

Method B. Methyl ^ -phthalimido-S-methyl-S-cephem ^ -carboxylate

A solution of 17.3 g (0.05 mol) of 7-phthalimido-3-methyl-3-cephem-4-carboxylic acid in 50 ml of acetone and 20 ml of water is slowly mixed with 5 g (0.05 mol) of potassium hydrogen carbonate. The resulting solution is evaporated to dryness, and 38 ml of dimethylformamide and 5 ml of methyl iodide are added to the residue. The mixture is stirred for 3 hours at room temperature. 100 g of ice are then added and the solid product obtained is filtered off. The product is recrystallized from a mixture of 100 ml of 2-propanol and 100 ml of acetone. This gives 7.91 g crystals, melting at 187-188 ⁰ C and have the following further characteristics: IR (CHCl ₃₎ 1790 and 1735 cm ^"1 NMR _(CDCl3) delta 2.31 (s, 3, CH ₃₎ 3.0 and 3.75 (ABq, 2, J = 15 Hz), 3.85 (s, 3, CH ₃ ), 5.15 (d, 1, J = 4.4 Hz), 5.74 (d, 1 , J = 4.4 Hz) and 7.73 (m, 4, ArH).

Analysis for C ₁₇ H ₁₄ N ₃ O ₅ S:

Calculated: C, 56.98; H 3.94; N 7.82; S 8.95; found: C, 56.75; H 3.66; N 7.53; S 8.89%.

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Method C. t -Butyl 7-phthalimido-3-methyl-3-cephem-4-carboxylate

A mixture of 13.76 g (40 mmol) of 7-phthalimido-3-methyl-3-cephem-4-carboxylic acid, 10 ml of concentrated sulfuric acid, 100 ml of dry dioxane and 50 ml of liquid isobutylene is stirred in a sealed pressure bottle at room temperature and then poured into excess ice cold aqueous sodium bicarbonate (44 g). Extraction of the mixture obtained with ethyl acetate and evaporation of the solvent gives a crude ester which is recrystallized from chloroform. The first harvest leads to 3.34 g of crystals which melt ^{at 189 to 191 ° C.} The second crop yields 1.72 g of crystals having a melting point 181-183 ⁰ C. The other characteristics of the material obtained are as follows: / alpha / _D = 77.7 ° (MeCN); IR (CHCl ₃ ) 1800, 1785 and 1735 cm "¹; NMR (CDCl ₃ ) delta 1.55 (s, 9, t-Bu); 2.23 -Cs, 3, CH ₃ ), 3.05 and 3 , 6 (ABq, 2, J = 16 Hz), 5.1 (d, 1, J = 4.5 Hz), 5.72 (d, 1, J = 4.5 Hz) and 7.8 (m , 4, ArH).

Analysis for C ₂₀ H ₃₀ N ₂ O ₅ S: '

calculated: C 59.99; H 5.03; N 7.00; 0 19.98; S 8.01; Found: C, 60.27; H 4.91; N 7.04; 0 20.06; S 7.74%.

Method D. t-Butyl 1-phthalimido-S-acetoxymethyl-S-cephem-4-carboxylate and t-butyl 7- (2-carboxybenzamido) -3-acetoxy-3-cephem-4-carboxylate

A mixture of 3.28 g (10 mmol) of t-butyl 7-aminocephalosporanate (7-ACA), 1.5 g (10 mmol) of phthalic anhydride, and 25 ml of benzene are added using a Dean-Stark water trap Heated to reflux for 2 hours. The solution is cooled with sodium carbonate (1.68 g in 20 ml of water), water and brine washed and finally dried. By evaporation

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of the solvent, 1.22 g of a neutral product are obtained. The product is chromatographed over silica gel using a gradient mixture of benzene and ethyl acetate. Fractions 54-87 give 330 mg of the phthalimido compound, which is recrystallized from dichloromethane / ether. The prisms obtained in this way melt at 176 to 178 ^° C. and have the following characteristics: ^ alpha / _D + 43.4 (MeCN); IR (CHCl ₃ ) 1800, 1785 and 1735 cm "¹; lambda _Ät0H 260 nyi (epsilon = 10 000); NMR (CDCl ₃ ) delta 1.55 (s, 9, t-Bu); 2.1 (s, 3, CH ₃ ), 3.5 (s, 2, CH ₂ ); 4.9 and 5.3 (ABq, 2, J = 14 Hz); 5.1 (d, 1, J = 4.5 Hz ); 5.82 (d, 1, J = 4.5 Hz) and 7.82 (m, 4, ArH).

Analysis for C ₂₂ H ₂₂ ^{K [} 2 ° 7 ^S:

calculated: C, 57.63; H 4.84; N 6.11; 0 24.43; S 6.99; Found: C, 57.56; H 4.60; N 6.31; 0 24.6O; S 6.9O%.

After removing the neutral product, the aqueous portion is acidified to pH 3.6 and the acidic mixture is extracted with ethyl acetate. Evaporation of the ethyl acetate gives 2.9 g of t-butyl 7- (2-carboxybenzamido) cephalosporanate. This material is dissolved in 50 ml of benzene, followed by the addition of 15 mg of imidazole and the mixture for 30 minutes using a Dean-Stark water trap heated to reflux. After working up and chromatography, 430 mg of t-butyl 7-phthalimidocephalosporanate are obtained.

The product ratio from the condensation of phthalic anhydride and the t-butyl ester of 7-ACA depends on the particular reaction time. You would get the mixture only 15 minutes then about 160 mg of the phthalimido compound would be obtained and about 4.34 g of the phthalamic acid compound.

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Method E. p-Methoxybenzyl 1-phthalimido-S-methyl-S-cephem-4-carboxylate

A suspension of 13.4 g (38 mmol) of T
cephem-4-carboxylic acid in 20 ml of dioxane and 10 ml of water is slowly mixed with 3.8 g of potassium hydrogen carbonate. The solution is evaporated to dryness and 100 ml of dimethylformamide and 8.8 g of p-methoxybenzyl bromide are added to the potassium salt residue. The mixture is stirred for 2 hours and then poured onto 200 g of ice. The mixture obtained is extracted twice with ethyl acetate. The extract is washed with water and brine, then dried and the solvent evaporated. The residue is recrystallized from ethyl acetate. This gives 4.1 g of large crystals which melt ^{at 118 to 121 ° C.} The second harvest yields 1.8 g of substance. The other physical data of the compound obtained in this way are as follows: / alpha / _D + 41.2 ° (MeCN), IR (CHCl ₃ ) 1800, 1785, 1745 and 1735 cm " ¹ , HMR (CDCl ₃ ) delta 2.15 (s, 3, CH ₃ ); 3.0 and 3.7 (ABq, 2, J = 15 Kz), 3.8 (s, 3, CH ₃ ), 5.11 (d, 1, J = 4 , 5 Hz), 5.28 (s, 2, CH ₂ ), 5.75 (d, 1, J = 4.5 Hz), 6.8-7.8 (m, 8).

Analysis for ^C 24 ^H 2O ^N 2 ° 6 ^S:

calculated: C, 62.06; H 4.34; N 6.03; 0 20.67; S 6.90; Found: C, 62.15; H 4.31; N 6.32; 0 20.88; S 6.82%.

example 1
7- (2-carboxybenzamido) -3-methyl-3-cephem-4-carboxylic acid

A solution of 7-phthalimido-3-methyl-3-cephem-4-carboxylic acid (3.44 g, 10 mmol) in 70 ml tetrahydrofuran at 0 ⁰ C with 80 ml of ice water and Na ₂ S.9H ₂ O (5 , 3 g, 22 mmol) are added. The whole is allowed to ^{stand for 20 minutes at 0 °} C., after which 10 ml of 1N hydrochloric acid are added and the volume of the mixture is then reduced to about 100 ml in vacuo. The aqueous solution is slurried with ethyl acetate (80 ml) and the pH is adjusted to 1.0 with concentrated hydrochloric acid. The organic layer is separated, washed with water (60 ml) and brine (50 ml), dried over magnesium sulfate and evaporated to dryness in vacuo. This gives 2.97 g (83%) 7- (2-carboxybenzamido) -3-methyl-3-cephem-4-carboxylic acid in the form of an amorphous solid, which has the following characteristics:

409881/1243

IR (KBr) 1772, 1730, 1720 and 1650 cm- ¹ ; NMR (DMSO ,,) 2.08 (s, 3,

d6 '1,

5.76 (dd, 1, J = 4.5 and 8.0 Hz) and 7.4 to 8.0 delta (m, 4, ArH).

CH ₃ ), 3.29 and 3.65 (ABq, 2, J = 19 Hz), 5.18 (d, 1, J = 4.5 Hz),

Analysis for C ₁ , H ₁ .N ₀ O, Si

Calculated: C, 53.05; H 3.89; N 7.73;
Found: C, 52.91; H 4.17; N 7.52%.

Example 2 7-Phthaloimido-3-methyl-3-cephem-4-carboxylic acid

A solution of 7- (2-carboxybenzamido) -3-methyl-3-cephem-4-carboxylic acid (376 mg, 1 mmol) in 15 ml of anhydrous tetrahydrofuran is treated at room temperature with sodium bicarbonate (420 mg, 5 mmol) and trifluoroacetic anhydride (0 , 33 ml, 2.25 mmol) were added. After 10 minutes the reaction mixture is filtered and the filtrate is evaporated to dryness. The product is taken up in about 10 ml of 5 percent sodium bicarbonate solution and washed with ethyl acetate (15 ml). The pH of the aqueous solution is adjusted to 2.4 with 1N hydrochloric acid in the presence of ethyl acetate (20 ml). The organic layer is separated, washed with brine (20 ml), dried over magnesium sulfate and evaporated to dryness in vacuo. The 7-phthalisoimido-3-methyl-3-cephem-4-carboxylic acid (240 mg, 67%) obtained in this way is a cream-colored amorphous solid which ^{melts at 179 to 180 °} C. (decomposition) and has the following additional characteristics: IR (KBr) 1818, 1770, 1731 and 1700 cm "¹; NMR (D ^ / HCO"); 2.03 (s, 3, _CH3); 3.20 and 3.78 (ABq, 2, H = 18 Hz); 5.44 (d, 1, J = 4 Hz), 4.85 (d, 1, J = 4 Hz) and 7.4 to 8.0 delta (m, 4, ArH).

Analysis for C ₁₆ H ₁₂ N ₂ O ₁ -S:

Calculated: C, 55.81; H 3.51; N 8.14; 0 23.23; S 9.31; Found: C, 55.97; H 3.62; N 8.15; 0 23.18; S 9.12 I.

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Example 3 7-Amino-3-methyl-3-cephem-4-carboxylic acid

A suspension of V-carboxylate (172 mg, 0.5 mmol) in tetrahydrofuran (7 ml) (1 mmol 0.032 ml) at 0 ⁰ C with anhydrous hydrazine was added. After 7 minutes, 1 η hydrochloric acid (2.5 ml) and water (2.5 ml) are added. The mixture is heated on a steam bath for 10 minutes, then cooled and concentrated in vacuo to a volume of about 5 ml. The aqueous solution is filtered and the pH of the filtrate is then adjusted to 3.7 with 5 percent sodium bicarbonate solution. After 15 minutes the solution is filtered to give 73 mg (68%) 7-amino-3-methyl-3-cephem-4-carboxylate. The spectral data and the values obtained in the thin-layer chromatogram show that the product of the process is identical to an authentic sample of 7-ÄDCä.

Example 4 Methyl 7- (2-carboxybenzamido) -3-methyl-3-cephem-4-carboxylate

A solution of 2.86 g (8 mmol) of methyl 7-phthalimido-3-methyl-3-cephem-4-carboxylate in 80 ml tetrahydrofuran is added at 0 ⁰ C with 2.4 g (1O mmol) of Na ₃ S ^ H ₃ O and 32 ml of ice water are added. The reaction mixture is on for 7 minutes

Maintained 0 C and then treated with 10 ml of 1 η hydrochloric acid. It is then evaporated to about 40 ml in vacuo and the aqueous solution obtained is washed with ethyl acetate. By adding

1 η hydrochloric acid is used to adjust the pH of the aqueous layer to 4.5 and then extracted with ethyl acetate (40 ml). The ethyl acetate layer is washed with brine (30 ml) washed, dried over magnesium sulfate and then evaporated to give 1.8 g of methyl 7- (2-carboxybenzamido) -3-

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methyl 3-cephem-4-carboxylate is obtained in the form of an amorphous colorless solid. Recrystallization from acetone leads to an analytical sample which melts at 182-184.5 C (decomposition) and has the following additional characteristics: IR (KBr) 1768, 1630, 1610 (shoulder) and 1665 cm "¹; NMR (CDCl ₃ / DMSO _{d- 6} ) 2.08 (s, 3, CH ₃ ), 3.12 and 3.52 (ABq, 2, J = 17 Hz), 3.8 (s, 3, CH ₃ ester), 5 , 06 (d, 1, J = 4.5 Hz), 5.86 (dd, 1, J = - 4.5 and J = 8.0 Hz) and 7.4 to 8.0 delta (m, 4th , ArH).

Analysis for C _1. , H ₁ gN-O ^ S:

calculated: C, 54.25; H 4.28; N 7.44; S 8.82; Found: C, 53.98; H 4.18; N 7.73; S 8.58.

The pH of the above aqueous solution is adjusted to 2.5 by adding 1 η hydrochloric acid, and the solution thus obtained is extracted with ethyl acetate (2 × 30 ml). The ethyl acetate extracts are combined, washed with brine (30 ml) and dried over magnesium sulfate. The ethyl acetate is evaporated in vacuo and a colorless crystalline product crystallizes out during this time. As soon as a volume of about 10 ml has been reached, the solution is filtered. This gives 190 mg (6.5%) 7- (2-carboxybenzamido) -S-methyl ^ -cephem ^ -carboxylic acid, which ^{melts at 196 198 0} C (decomposition) and has the following additional characteristics: IR (KBr) 1773, 1700 and 1658 cm "¹; NMR (DMSO _d6 ) 1.88 (s, 3, CH ₃ ), 4.64 (s, 1, C ₄ -H), 5.15 (d, 1, J = 4, OHz), 5.5 (dd, 1, J = 4.0 and 8.0 Hz), 6.15 (s, 1, C ₂ -H) and 7.4 to 8.0 delta (m, 4, ArH).

Analysis for C ₁₆ H .. .ISuOgS:

Calculated: C, 53.03; H 3.89; N 7.73; S 8.85; Found: C, 52.76; H 3.85; N 7.68; S 8.77%.

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Evaporation of the filtrate obtained above leads to another 600 ml of methyl 7- (2-carboxybenzamido) -3-methyl-3-cephem-4-carboxylate. The total yield is therefore 80% .. ■ "-

Example 5 Methyl · -? - phthalisoimido-S-methyl-S-cephem ^ -carboxylate

A solution of 1.88 g (5 mmol) of methyl 7- (2-carboxybenzamido) -S-methyl-S-cephem ^ -carboxylate in 40 ml of dry dioxane is at room temperature with 1.52 ml (11 mmol) of triethylamine and 0.81 ml (5.5 mmol) of trifluoroacetic anhydride were added. The mixture is filtered for 30 minutes at room temperature and then poured into 180 ml of ice water, after about 5 minutes the aqueous mixture is filtered and the cream-colored product obtained (1.60 g, no impurities in the NMR spectrum, yield of crude product 89% ) is dried in vacuo. By recrystallization from acetone, 1.44 g (80%) of methyl 7-phthalisoimido-3-methyl-3-cephem-4-carboxylate at 191 - 193 ⁰ C melts and has the following further characteristics: IR (KBr ) 1798, 1771, 1730 and 1710 cm "¹; NMR (CDCl ₃ ); 2.19 (s, 3, CH ₃ ), 3.19 and 3.60 (ABq, 2, J = 18 Hz); 3, 85 (s, 3, CH ₃ ester); 5.13 (d, 1, J = 4.5 Hz); 5.80 (d, 1, J = 4.5 Hz) and 7.6 to 8.28 (m, 4h, ArH)

Analysis for C ₁ -H ₁₄ W ₂ O ₅ S:

Calculated: C, 56.98; H 3.94; N 7.82; 0 22.32; S 8.95; found: C, 56.83; H 3.83; "N 7.81; 0 22.50; S 8.94.

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Example 6 Methyl 7-amino-3-methyl-3-cephem-4-carboxylate hydrochloride

Anhydrous hydrazine (0.053 ml, 97%, 1.6 mmol) becomes a Suspension of

carboxylate (570 mg, 1.6 mmol) in 15 ml of tetrahydrofuran at 0 ° C. The batch is ^{kept at 0 °} C. for 10 minutes, after which the mixture is evaporated to dryness in vacuo. The residue is taken up in a mixture of 3 ml of tetrahydrofuran and 2.3 ml of 1 η hydrochloric acid. The mixture is heated on a steam bath for 5 minutes and allowed to slowly cool to room temperature. By filtration of the mixture leads to 210 mg of a colorless crystalline product which was as Diketophthalazin (m.p. 339-343 ⁰ C) is identified. The filtrate (volume of about 10 ml obtained on washing the precipitate) is evaporated in vacuo to a volume of about 5 ml. The gummy material formed on the walls of the flask is washed with 5 ml of water and then discarded. The wash liquors are combined with the remainder of the filtrate from above and the total mixture is evaporated in vacuo to give a light yellow amorphous product (260 mg, 62%). The thin-layer chromatogram shows only small amounts of impurities. Recrystallization from ethanol / ethyl ether to obtain an analytical sample at 173 - melt 179 ⁰ C (decomposition) and has the following further characteristics: IR (KBr) 1770 and 1734 cm ~ ^1; NMR (DMSO _{d- 6} ), 2.18 (s, 3, CH ₃ ), 3.62 (broad s, 2, methylene), 3.78 (s, 3, CH ₃ ester), 5.06 (d , 1, J = 4.5 Hz) and 5.21 delta (d, 1, J = 4.5 Hz).

Analysis for C ₉ H ₁₃ N ₂ O ₃ SCl:

Calculated: C 40.82; H 4.95; N 10.58; S 12.11; Cl 13.39; Found: C, 40.83; H 4.78; N 10.84; S 12.05; Cl 13.49%.

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To prepare the corresponding free amine, an aqueous solution of the hydrochloride prepared is adjusted to pH 8.0 with sodium bicarbonate, and the solution is then extracted with ethyl acetate. The ethyl acetate solution is dried over magnesium sulfate and then evaporated to dryness. This gives a pale yellow, resinous product which is identified as methyl 7-amino-3-methyl-3-cephem-4-carboxylate and has the following characteristics: NMR '(CDCl-), 2.11 (s, 3, CH ₃ ), 2.54 (broad s, 2, MH ₂ ), 3.13 and 3.56 (ABq, 2, J = 18 Hz), 3.83 (s, 3, CH ₃ ester), 4, 69 (d, 1, J = 4.6 Hz) and 4.93 delta (d, 1, J = 4.6 Hz).

Example 7

t-Butyl-7- (2-carboxybenzamido) -S-acetoxymethyl-S-cephem ^ -

carboxylate

A solution of 458 mg (1 mmol) of t-butyl-7-phthalimido-3-acetoxymethyl-3-cephem-4-carboxylate in 10 ml of tetrahydrofuran is cooled in an ice-water bath and then with 1.1 ml of 1 η Sodium hydroxide added. After stirring for 5 minutes, 10 ml of water and 30 ml of ethyl acetate are added. The ethyl acetate layer is separated and 70 mg of starting material is recovered from it. The aqueous layer is acidified to pH 4.0 and the acidified layer is extracted with ethyl acetate. After working up, 330 mg (83%) of the desired phthalamic acid are obtained, which has the following characteristics: / alpha / + 26.37 (MeCN); lambda ^. 260 m, u (epsilon 8800); IR (CHCl ₃ ) 1785, 1730 and 1685 cm "¹; NMR (CDCl ₃ ) delta 1.55 (s, 9, t-Bu), 2.05 (s, 3, Ac), 3.3 and 3, 6 (ABq, 2, J = 17 Hz), 4.72 and 5.2 (ABq, 2, J = 14 Hz), 4.98 (d, 1, J = 4.5 Hz), 5.9 ( dd, 1, J = 4.5 and 9 Hz) and 7.5-8 (m, 4, ArH).

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Example 8 t -Butyl ^ -phthalisoimido-S-acetoxymethyl-S-cephem ^ -carboxylate

A solution of 476 mg (ImMoI) t-butyl-7- (2-carboxybenzamido) -3-acetoxymethyl-3-cephem-4-carboxylate and 0.14 ml (1 mmol) triethylamine in 10 ml dry tetrahydrofuran is brought to -20 ⁰ C cooled, and then mixed with 0.1 ml of ethyl chloroformate. The mixture is stirred 20 minuntes at -20 ⁰ C and then 1O minutes at room temperature. The solvent is then evaporated and the residue is dissolved in chloroform. The solution is washed with sodium bicarbonate solution, water and brine, and then dried, whereupon the solvent is evaporated off to obtain 365 mg of the isoimide.

Example 9,

t -Butyl 7-amino-3-acetoxymethyl-3-cephem-4-carboxylate

A solution of 916 mg (2 mmol) of t-butyl 7-phthalisoimido-3-acetoxymethyl-3-cephem-4-carboxylate in 15 ml of dry tetrahydrofuran is cooled in an ice-water bath and then with 0.078 ml of anhydrous hydrazine were added. The mixture is stirred for 5 minutes, after which it is concentrated to a volume of 5 ml and then 3 ml of 1 η hydrochloric acid are added. The mixture is refluxed for 2-3 minutes and then to room temperature cooled down. The precipitated diketophthalazine is filtered off, and the filtrate is evaporated to dryness, whereby 410 mg (55%) of the hydrochloride salt are obtained. By treating with sodium bicarbonate and extracting with chloroform this salt is converted to the free amine. The melting point as well as the IR and NIIR spectra agree with an authentic one Sample prepared according to the method of R. J. Stedmann, J. Med. Chem., (1966) page 444 became.

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Example 10 t-Butyl-7- (2 - bhienylacetamido) -3-acetoxymethyl-3-cephem-4-

carboxylate

A solution of 1.37 g. (3 mmol) of t-butyl-7-phthalisoimido-3-aeetoxymethyl-3-cephem-4-carboxylate in 10 ml .trockenem tetrahydrofuran is cooled in an ice-water bath and then 0.12 ml of anhydrous hydrazine is added. The equipment is stirred for 5 minutes, then 0.75 ml of 2-thienylacetyl chloride are added, whereupon the mixture is refluxed for 8 minutes, cooled and evaporated to dryness. The residue is dissolved in ethyl acetate and the solution obtained is washed, one after the other with sodium bicarbonate solution, 1 η hydrochloric acid, water and brine. The crude mixture is chromatographed over silica gel using a gradient mixture of benzene and ethyl acetate. Fractions 16 to 73 are collected and they give 340 mg of t-butyl ester of cephalothin with the following characteristics: / alpha / - + 40.0 ° (MeCN); lambda _ÄtGH 238 and 262 m, u (epsilon 14 200 and 8300); IR (CHCl ₃ ) 1785, 1740, 1730 and 1690 cm ^-1 ; NMR (CDCl ₃ ) delta 1.55 (s, 9, t-BuJ, 2.1. (S _r 3, CH ₃ ), 3.25 and 3.6 (ABq, 2, J = 17 Hz), 3 , 82 (s, 2, CH ₂ ), 4.75 and 5.14 (ABq, 2, CH ₃ ), 4.92 (d, 1, J = 4.5 Hz), 5.82 (dd, 1 , J = 4.5 and 9 Hz) and 7.2 (m, 3, ArH).

Analysis for C ₂₀ H ₂₄ N ₂ O ₆ S ₂ :

Calculated: C, 53.08; H 5.35; N 6.19; 0 21.21; S 14.17; Found: C, 52.84; H 5.10; N 6.30; 0 21.46; S 13.92%,

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Example 11 t -Butyl 7- (2-carboxybenzamido) -3-methyl-3-cephem-4-carboxylate

A solution of 800 mg (2 mmol) of t-butyl 7-phthalimido-3-methyl-3-cephem-4-carboxylate in 25 ml of tetrahydrofuran and 8 ml of water is cooled in an ice bath. _{660 mg Na 2} S.9H ₂ O _{f are} added to the solution, and the resulting mixture is stirred and cooled for 10 minutes. At the end of this time 10 ml of water are added and the mixture is extracted with 40 ml of ethyl acetate. The extract is discarded. The aqueous portion is acidified to pH 4.3 with 1 η sulfuric acid and then extracted with ethyl acetate. The ethyl acetate extract is dried and evaporated to give 700 mg of the title compound. The product is recrystallized from chloroform / cyclohexane, and then it has a melting point of 178-179 ⁰ C, and the following additional physical characteristics: IR (Nujol) 1770, 1735 and 1680 cm ^"1; NMR _(CDCl3 + DMSO _dg) delta 1.5 (s, 9, t-Bu), 2.1 (s, 3, CH ₃ ), 3.2 and 3.5 (ABq, 2, J = 18 Hz), 5.02 (d, 1 , J = 4.5 Hz), 5.82 (dd, 1, J = 4.5 and 9 Hz) and 7.4 to 8 (m, H, ArII).

Analysis for ^c ₂ o ^H 22 ^W 2 ° 6 ^S:

calculated: C, 57.40; H 5.30; N 6.69; 0 22.94 and S 7.66; found: C, 57.70; H 5.20; N 6.52; 0 22.72 and S 7.53%.

An identical substance (NMR, IR, melting point) can also be obtained from phthalic anhydride in 94 percent yield and the t-butyl ester of 7-ADCA.

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Example 12 t -Butyl 7-phthalisoimido-3-π-methyl-3-cephem-4-carboxylate

A mixture of 4.13 g (10 mmol) of t-butyl-7- (2-carboxybenzamido) -S-methyl-S-cephem - ^ - carboxylate, 40 ml of dry tetrahydrofuran (THF) and 1.39 ml (10 mmol ) Triethylamine is cooled in an ice-salt bath. A solution of 1.0 ml (10.5 mmol) of ethyl chloroformate in 10 ml of dry tetrahydrofuran is then added, and the resulting mixture is stirred and cooled for 20 minutes. The mixture is then warmed to room temperature and stirred for an additional 20 minutes. The precipitated salt (Ät_N.HCl) is filtered off, and the filtrate is evaporated to dryness. The residue obtained is dissolved in lithyl acetate, whereupon the solution is washed with water and salt solution. The resulting solution is then heated to boiling and the solvent is removed. The residue obtained (3.93 g or 98%) is pure isoimide. A sample (1 O g) is obtained from acetonitrile (5 ml) to give to give silky needles (570 mg), at 179 - 180 ⁰ C melt and have the following further characteristics: / alpha / -128.7 ° (MeCN); IR (KBr) 1810, 1775, 1730 and 1710 cm "¹; NMR (CDCl ₃ ) delta 1.55 (s, 9Vt-Bu); 2.15 (s, 3, CH ₃ ); 3.18 and 3, 59 (ABq, 2, J = Hz); 5.15 (d, 1, J = 4.5 Hz); 5.18 (d, 1, J = 4.5 Hz) and 7.65 to 8.05 (m, 4, ArH).

Analysis for C ₂₀ H ₂₀ N ₂ O ₅ S:

calculated: C, 59.96; H 5.03; N 7.00; S 8.01; found: C, 59.66; H 4.74; N 7.40; S 7.87%.

40 98 81/1243

Example 13
t -Butyl 7-amino-3-methyl-3-cephem-4-carboxylate

A solution of 400 mg (1 mmol) of t-butyl 7-phthalisoimido-3-methyl-3-cephem-4-carboxylate in 15 ml of dry tetrahydrofuran is cooled in an ice-water bath. 0.04 ml of anhydrous hydrazine is added to the solution while stirring,
which is then stirred for a further 5 minutes. The resulting mixture
is acidified by adding 2.5 ml of 1 η hydrochloric acid. After briefly refluxing, a major part of the tetrahydrofuran is evaporated on a rotary evaporator. The diketophthalazine which has precipitated is filtered off and washed with 10 ml of water, whereupon it is filtered again and the filtrate is evaporated to dryness. The remaining hydrochloride salt (270 mg, 88%) is under
Converted to the free amino ester using ethyl acetate and sodium bicarbonate. This is a colorless solid at 118 - 120 ⁰ C melts and more the following
Features: / alpha / + 76.3 ° (HeCN); lambda
(EtOH) 268 mu (epsilon 6350), IR (CHCl ₃ ) 1790 and
1735 cm "¹; NMR (CDCl ₃ ) delta 1.52 (s, 9, t-Bu), 2.1 (s,
3, CH ₃ ), 3.17 and 3.64 (ABq, 2, J = 18 Hz) and 4.7 (d, 1,
J = 4.5 Hz) and 4.93 (d, 1, J = 4.5 Hz).

Analysis for C ₁₂ H ₁₈ N ₃ O ₃ S:

Calculated: C, 53.31; H 6.71; M 10.36; 0 17.75; S 11.86;
Found: C, 53.35; H 6.45; N 10.12; 0 18.05; S 12.09%.

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Example 14

p-iiethoxybenzyl ^ - ^ - carboxybenzamidol-S-methyl-S-cephem ^ -

carboxylate

A solution of 930 mg (2 mmol) of p-methoxybenzyl-7-phthalimido-3-methyl-3-cephera-4-carboxylate in 25 ml of tetrahydrofuran and 8 ml of water is cooled in an ice-water bath and then with 660 mg Na ₂ S.9H ₂ O added. The mixture is stirred for 15 minutes, after which 10 ml of water and 40 ml of ethyl acetate are added. The layers are separated and 140 mg of a neutral material is obtained from the ethyl acetate layer. The aqueous layer is acidified to pH 4.3 with 1 η sulfuric acid and extracted twice with ethyl acetate. The ethyl acetate extract is washed, dried and evaporated to dryness. This gives 660 mg (68%) of the phthalamic acid in the form of an amorphous solid which has the following characteristics: / alpha / _Q + 85.6 ° (MeCN); IR (CHCl ₃ ) 178.1, 1740 and 1710 'can'¹; NMR (CDCl ₃ ) delta 2.08 (s, 3, CH ₃ ), 3.1 and 3.43 (ABq, 2, J = 17 Hz), -3.79 (s, 3, CH ₃ ), 5 , 0 (d, 1, J = 4.5 Hz), 5.1 (s, 2, CH ₂ ), 5.8 (dd, 1, J = 4.5 Hz), 6.75 to 7.6 (m, 8).

Analysis for C ₂₄ Ii ₂₂ N ₂ O ₇ S:

Calculated: C, 59.74; H 4.60; N 5.81; 0 23.21; S 6.65; Found: C, 59.81; H 4.32; N 6.07; 0 23.34; S 6.51%.

Example 15 p-Methoxybenzyl ^ -phthalisoimido-S-methyl-S-cephem ^ -carboxylate

A mixture of 400 mg (0.8 mmol) p-methoxybenzyl-7- (2-carboxybenzamido) -3-methyl-3-cephem-4-carboxylate, 15 ml of dry tetrahydrofuran and 0.110 ml of triethylamine are added to an ice-salt bath

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cooled and then treated with 0.08 ml of ethyl chloroformate. The mixture is stirred for 25 minutes and cooled. The precipitated salt of At ₃ N-HCl is filtered off. The filtrate is evaporated to dryness and the residue is dissolved in chloroform. The solution obtained is washed and dried, giving 300 mg of an amorphous solid product with the following characteristics: lambda (ÄtOH) 265 m, u (epsilon 8800), IR (CHCl-) 1820, 1785, 1735 and 1715 cm ', NMR (CDCl ₃ ) delta 2.15 (s, 3, CH ₃ ), 3.15 and 3.55 (ABq, 2, J = 18 Hz), 4.00 (s, 3, CH ₃ ), 5.18 (alpha, 1, J = 4.5 Hz), 5.3 (s, 2, CH ₃ ), 5.78 (d, 1, J = 4.5 Hz) and 6.8 to 8 (m, 8 , ArH).

Analysis for C ₂₄ H ₂₀ N ₂ OgS:

calculated: C, 62.06; H 4.34; N 6.03; 0 20.67; S 6.90; Found: C, 62.18; H 4.34; N 6.26; 0 20.66; S 6.98%.

Example 16

p-Methoxybenzyl ^ -amino-S-iethyl-S-cephem ^ -carboxylate-p-toluene-

sulfonic acid salt

A solution of 190 mg (0.4 ral-lol) p-methoxybenzyl-7-phthalisoimido-3-methyl-3-cephem-4-carboxylate in 10 ml of dry tetrahydrofuran is at room temperature with 0.017 ml of anhydrous Hydrazine added. The mixture is stirred for 5 minutes and then evaporated to dryness. The residue is dissolved in 2.0 ml 75 percent aqueous acetonitrile, and the solution is added one with 90 mg of p-toluenesulfonic acid monohydrate. The mixture will heated to reflux, whereby diketophthalazine begins to precipitate. The mixture is cooled to room temperature and the precipitate is filtered off. The filtrate is evaporated, and the residue is treated with ether. This gives 190 mg of the title compound. This material is similar to that of

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Chavette et. al. in "J. Org. Chem., 36, 1265 (1971) Material identical.

Example 17

p-Nitroben2yl-7- (2-carboxybenzamido) -3-methyl-3-cepheni-4-- ■ "" · - " carboxy lat

An ice-cold solution of 480 mg (1 mmol) of p-nitrobenzyl-7-phthalimido-3-methyl-3-cephem-4-carboxylate in 25 ml of tetrahydrofuran and 5 ml of water is mixed _{with 340 mg of sodium sulfide (Na 2 p.9-} H ₂ H) added. The mixture is stirred for 7 minutes at pH 11.5 and then 40 ml of ethyl acetate and 10 ml of water are added. The layers are separated and the organic layer is washed with 5 ml of water and 5 ml of brine to give 150 mg of a neutral material. The aqueous layer is acidified to pH 4.5 with 1N sulfuric acid and the emulsion obtained is extracted with 25 ml of ethyl acetate. The extract is washed with brine, dried and evaporated to dryness. This gives 290 mg of crude product, from which 150 mg (30%) of pure product are obtained.

The same compound can also be prepared by another method by adding phthalic anhydride and the Heated p-nitrobenzyl ester of 7-ADCA in acetonitrile to reflux for 30 minutes.

A sample is recrystallized from dioxane / water, and the resulting colorless crystals melt at 192 to 193 C and have the following additional characteristics:

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NMR (DMSO-dg) delta 2.04 (s, 3, CH ₃ ), 3.35 and 3.68 (ABq, 2, J = 18 Hz), 5.2 (d, 1, J = 4 Hz, H-6), 5.4 (s, 2, CH ₃ ), 5.8 (dd, 1, J = 4.5 and 9Hz), 8 (m, 8 ArH).

Analysis for C ₂₃ H ₁₉ N ₃ OgS:

Calculated: C, 55.53; H 3.85; N 8.45; O 25.73; S 6.45; Found: C, 55.67; H 3.94; N 8.49; O 25.89; S 6.47%.

The subsequent acidification of the aqueous solution to pH 2.0 and subsequent extraction with ethyl acetate gives 120 mg p-Nitrobenzyl-7- (2-carboxybenzamido) -S-methyl - ^ - cephem - ^ - carboxylate.

Example 18

p-Nitrobenzyl-7-phthalisolmido-3-n-ethyl-3-cephem-4-carboxylate A. Use of ethyl chloroformate

p-Nitrobenzyl-7- (2-carboxybenzamido) -3-methyl-3-cephem-4-carboxy lat (10 g, 20 mmol) and 2.8 ml (20 mmol) of triethylamine are dissolved in 200 ml of dry tetrahydrofuran. The mixture is treated with 2.0 ml (20 mmol) of ethyl chloroformate while stirring and cooling in an ice bath. The mixture is then stirred for a further 20 minutes in an ice bath and 10 minutes at room temperature. The salt (At ₃ N-HCl) thus obtained is filtered off and the filtrate is evaporated to dryness. The yield of the crude product is 4.6 g. Recrystallization from acetonitrile gives long

> egg

colorless needles which melt at 204 to 205 ⁰ C; IR (KBr) 1821, 1785, 1730 and 1710 cm

Analysis for C ₃₃ H ₁₇ N ₃ O ₇ S:

calculated: C, 57.62; H 3.57; N 8.76; 0 23.36; S 6.69; Found: C, 57.42; H 3.53; N 8.99; 0 23.64; S 6.66%.

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B. Use of trifluoroacetic anhydride

A solution of 1.0 g (2 mmol) of p-nitrobenzyl 7- (2-carboxybenzamido) -3-methyl-3-cephem-4-carboxylate and 0.34 ml (2.6 mmol) of triethylamine in 25 ml of dioxane is placed in an ice-water bath chilled. The mixture is then admixed with 0.36 ml (2.6 ~ mmol) of trifluoroacetic anhydride while stirring. One stirs another 30 minutes and then add 10 ml of water. The unusual one. Isoimide is filtered off and dried. The yield is 840 mg (87%). The product is re IR spectrum and melting point identical to the material produced by method Ä.

Example 19 p-Nitrobenzyl-7-amino-3-methyl-3-cephem-4-carboxylate hydrochloride

A solution of 960 mg (2 mmol) of p-nitrobenzyl-7-phthalisoimido-S-methyl-S-cephem ^ -carboxylate in 30 ml of dry tetrahydrofuran is cooled in an ice-water bath and then 0.075 ml of anhydrous hydrazine is added. The mixture is stirred for 5 minutes and about 20 ml of the solvent is removed on a rotary evaporator. About 4 ml of 1 η hydrochloric acid are added to the mixture obtained, and the mixture is stirred on a steam bath for 5 minutes. The warm mixture leaves you 30 minutes at room temperature, after which the precipitated Diketophthalazin (melting point 340 to 343 ⁰ C) was filtered off. The filtrate is evaporated to dryness, and 750 mg (98%) of the dihydrochloride salt of 7-ADCA-p-nitrobenzyl ester are obtained in this way.

40 9 8-81 / 1243

Example 20 p-Nitrobenzyl ^ -phenylacetamido-S-methyl-S-cephem- ^ - carboxylate

A suspension of p-Nitrobenzy1-7-phthalisoimido-3-methyl-3-cephem-4-carboxylate (480 mg, 1 mmol) in tetrahydrofuran (0.033 ml, 1.06 mmol) at 0 ⁰ C with anhydrous hydrazine was added. After 10 minutes the mixture is evaporated to dryness. The residue is taken up in acetone (15 ml) and tetrahydrofuran (15 ml) and phenylacetyl chloride (0.28 ml, 2.2 mmol) is added. After refluxing for 30 minutes, the mixture is cooled and evaporated to dryness in vacuo. The product is taken up in chloroform (50 ml), after which it is washed in sequence with 1 η hydrochloric acid (30 ml), 10 percent sodium bicarbonate (40 ml) and brine (40 ml), dried over magnesium sulfate and dried to dryness in vacuo evaporates. The colorless product is slurried with ethyl acetate (12 ml). Filtering off gives p-nitrobenzyl-7-phenylacetamido-3-methyl-3-cephem-4-carboxylate (280 mg, 60%). Recrystallization from ethyl acetate leads to an analytical sample at 227 - melt 230 ⁰ C and has the following further characteristics: IR (KBr) 1772, 1732 and 1652 cm ^"1; NMR (CDCl ₃ / DMSO _d _ ₆₎ 2 , 17 (s, 3, CH ₃ ), 3.23 and 3.54 (ABq, 2, J = 17 Hz), 3.62 (s, 2, side chain CH ₂ ), 4.98 (d, 1, J = 4.5 Hz), 5.39 (s, 2, ester CH ₂ ), 5.60 (dd, 1, J = 4.5 and 8.0 Hz), 7.34 (s, 5, ArH ) and 7.90 (m, 4, ArH).

Analysis for C ₃₃ H ₂₁ N ^ OS:

Calculated: C, 59.09; H 4.53; N 8.99; 0 20.53; S 6.86; Found: C, 58.92; H 4.24; N 9.21; 0 20.40; S 6.64.

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- 45 -

Example- 21

t-Butyl-7- (3 '-carboxy) acrylamido-S-acetoxymethyl-S-cephenv-

4-carboxylate

A solution of 656 mg (2MoI) of t-butyl ^ -amino-S-acetoxymethyl-3-cephem-4-carboxylate and 196 mg (2 mmol) of maleic anhydride in 20 ml of benzene is refluxed for 0.5 hours, then cooled and evaporated to dryness in vacuo. The thin-layer chromatographic examination shows that there is no starting material and only a slowly moving product is present, which has the following characteristics: ONLY (CDCl ₃ ) 94 (s, 9, t-Bu), 127 (s, 3, OAc), 207 and 216 (ABq, 2, J = 20 Hz), 293 and 307 (ABq, J = 14.0, CH ₂ OAc), 305 (1, d, J = 4.5, azetidinone H), 350 (1 , q, J = 4.5 and 8.0 Hz, azetidinone H), 390 (2H, q, J = 12 and 2.0 Hz), 534 (1, d, J = 8.0, NH) and 806 Kz (1, broad, s, COOH).

B e i s ρ i e 1 22

t-Butyl ~ 7-isomaleimido-3-acetoxymethyl-3-cephem-4-carboxylate A. Use of N, N'-dicyclohexylcarbodiimide

A solution of 2.13 g (5 mmol) of t-butyl 7- (3'-carboxy) acrylamido-3-acetoxymethyl-3-cephem-4-carboxylate in 150 ml of methylene chloride is mixed with 1.02 g (5 mmol) N, N ¹ -dicyclohexylcarbodiimide added. The resulting solution is stirred for 1 hour at room temperature, whereupon it is filtered off and the filtrate is evaporated to dryness in vacuo. The residue obtained is taken up in ethyl acetate (40 ml) and washed in sequence with dilute hydrochloric acid, water, 10 percent sodium bicarbonate solution and brine and finally dried over magnesium sulfate.

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2423184

Evaporation of the mixture in vacuo gives a brown foam (1.85 g). The NMR spectrum (CDCl ₃ ) shows a clean sample of t-butyl-T-isomaleimido-S-acetoxymethyl-S-cephem-4-carboxylate, which has the following characteristics: NMR (CDCl ₃ ) 93 (9 _f s, t-Bu), 125 (3, s, OAc) 204 and 216 (2, ABq, J = 18 Hz), 291 and 305 (2, ABq, J = 14 Hz, CH ₂ OAc), 306 (1, i.e. , J = 4.5 Hz, 346 (1, d _f J = 4.5 Hz, azetidinone H), 405 and 444 (2, d, J = 6 Hz (isomaleimide H).

B. Use of trifluoroacetic anhydride

A solution of 852 mg (2 mmol) of t-butyl 7- (3'-carboxy) acrylamido-3-acetoxymethyl-3-cephem-4-carboxylate in 25 ml of tetrahydrofuran is mixed with 0.28 ml (2 mmol) of triethylamine at room temperature and then 0.30 ml (2 mmol) of trifluoroacetic anhydride are added. The whole is left at room temperature for 20 minutes, after which the reaction mixture is evaporated to dryness in vacuo. The crude product obtained is taken up in 20 ml of ethyl acetate and washed in sequence with water, 10 percent sodium bicarbonate solution and brine and finally dried over magnesium sulfate. Evaporation in vacuo gives 530 mg of a brown foam which is identified as t-butyl-T-isomaleimido-S-acetoxymethyl-S-cephem ^ - carboxylate, which has the following physical characteristics: NMR (CDCl ₃ ) 93 (9 , s, t-Bu), 125 (3, s, OAc), 204 and 216 (2, ABq, J = 18 Hz), 291 and 3O5 (2, ABq, J = 14 Hz, CH ₂ OAc), 306 (1, d, J = 4.5 Hz), 346 (1, d, J = 4.5 Hz, azetidinone H) and 405 and 444 (2, d's, J = 6, isomaleimide H).

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Example 23

t-Butyl-T-amino-S-acetoxymethyl-S-cephem ^ -carboxylate

A solution of 408 mg (1 mmol) of t-butyl-V-S-isomaleimido acetoxyrnethyl-3-cephem-4-carboxylate in 15 ml tetrahydrofuran is added at 0 ⁰ C and 0.032 ml (1 mmol) of anhydrous hydrazine. It leaves the whole iO minutes at 0 C _f whereupon the Reaktionsgernisch evaporated to dryness. The residue is dissolved in a mixture of 4 ml of tetrahydrofuran and 2.5 ml of 1 η hydrochloric acid, and the resulting mixture is heated on a steam bath for about 3 minutes. The mixture is then left to stand at room temperature for 0.5 hours, after which the tetrahydrofuran is removed in vacuo and 10 ml of water are added. The acidic aqueous layer is washed with ethyl acetate (2 × 10 ml). Ethyl acetate (15 ml) is then added and the pH of the aqueous layer is adjusted to 8.0 with sodium bicarbonate. The organic layer is separated, washed with brine and dried over magnesium sulfate. Evaporation in vacuo gives 75 mg of a tan amorphous product. The values obtained by thin-layer chromatographic analysis and by NMR measurement show that the product is identical to authentic t-butyl-T-amino-S-acetoxymethyl-S-cephem-4-carboxylate.

Example 24 Benzhydryl 6- (2'-carboxybenzamido) penicillinate

A solution of benzhydryl e-phthalimidopenicillinate (2.56 g, 5 mmol) in 50 ml of tetrahydrofuran is mixed with 1.35 g (5.5 mmol) of Na ₂ S.9H ₂ O and 50 ml of ice water at 0 ° C. The mixture is left the whole 10 minutes at 0 ⁰ C, followed by 5 ml of 1, On adding hydrochloric acid and the mixture in vacuo to a volume of

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Concentrate about 50 ml and wash with 2 χ 50 ml of ethyl acetate each time. The pH of the aqueous layer is adjusted to 4.0 with concentrated hydrochloric acid and then extracted with 50 ml of ethyl acetate. The ethyl acetate layer is washed with brine and dried over magnesium sulfate. Evaporation in vacuo gives benzhydryl 6- (2'-carboxybenzamido) penicillinate in the form of a colorless foam, which has the following characteristics: NMR (CDCl ₃ ) 73 (3, s), 92 (3, s), 269 ( 1, s, H-3), 335-355 (2, m, acetidinone H), 413 (1, s,

(C _C H _C ) _O CH) and 430-480 Hz (14, m, ArH). . 0 0 ζ

Example 25

Benzhydryl-6-phthalisoimidopenicillinate A. Use of trifluoroacetic anhydride

A solution of 530 mg (1 mmol) of benzhydryl 6- (2'-carboxybenzamido) penicillinate in 10 ml of dry dioxane is mixed with 0.14 ml (1 mmol) of triethylamine and 0.15 ml (1 mmol) of trifluoroessgic anhydride. The whole is left for 10 minutes at room temperature, after which the reaction mixture is poured into 50 ml of ice water (+ about 20 g of ice). After the ice has melted in the aqueous mixture, the light yellow precipitate is filtered off. After drying, this gives 290 mg of a yellow amorphous solid. The NMR spectrum of this product confirms the presence of Benzhydry1-6-phthalisoimidopenicillinate, which has the following physical characteristics: NMR (CDCl ₃ ) 77 (3, s), 99 (3, s), 278 (1, s, H- 3), 342 (2, q, J = 4.0, azetidinone H), 420 (1, s, (CgH ₅ ) ₂ CH) and 430-490 (14, m, ArH).

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B. Use of NyN'-dicyclohexylcarbodiimide

A solution of 265 mg (0.5 mmol) of benzhydryl 6- (2'-carboxybenzamido) penicillinate 102 mg (0.5 mmole) of N, N'-dicyclohecylcarbodiimide are added to 7 ml of methylene chloride. 2 <after 0.5 hours long standing at room temperature, the reaction mixture is filtered, whereupon the filtrate is evaporated in vacuo. That The NMR spectrum shows that this crude product is a clean sample of Benzhydry1-6-phthalisoimidopenicillinate acts.

Example .26 Benzhydry1-6 -aminopenicillinate

A solution of 1 mllol benzhydryl-6-phthalisoimidopenicillinat in 35 ml · dry tetrahydrofuran is added at -76 ⁰ C with a solution of 0.053 ml (1 mmol) of methylhydrazine in 5 ml of tetrahydrofuran. The solution is then removed from the dry ice-acetone bath and allowed to warm to room temperature over a period of 1 hour. The reaction mixture is evaporated to dryness in vacuo and the product obtained is taken up in 25 ml of chloroform. The mixture is allowed to stand for 1 hour at room temperature, and during this time falls Methylphthalhydrazid (m.p. 243-245 ⁰ C). A light-colored foam is obtained by filtering off and evaporating the filtrate in vacuo. It is taken up in 20 ml of ethyl acetate and then extracted twice with 10 ml of 0.05 η hydrochloric acid. The aqueous acidic extracts are combined and added dropwise to a slurry of 25 ml of ethyl acetate and 25 ml of 10 percent strength sodium bicarbonate solution. The organic layer is separated with brine

4 09881/1243

washed and dried over magnesium sulfate. Evaporation gives a colorless foam. The results thin layer chromatography and the NMR spectrum of the Foams are consistent with the structure of the title compound.

Example 27 6-Phthalisoimidopenicillanic Acid A. Use of Trifluoroacetic Anhydride

A solution of 364 mg (1 mmol) 6- (2'-carboxybenzamido) penicillanic acid in 15 ml dry dioxane is treated with 0.42 ml (3 mmol) triethylamine and then 0.30 ml (2 mmol) trifluoroacetic anhydride at room temperature. After 15 minutes, the yellow reaction mixture is poured into a mixture of 50 ml of water. 20 g of ice and 0.07 ml (0.5 mmol) of triethylamine. The finely divided precipitate which forms is filtered off, washed with water and dried in vacuo. This gives 190 mg of a light yellow amorphous solid. The NMR spectrum shows traces of 6-phthalimidopenicillanic acid, but the main product is 6-phthalimidopenicillanic acid, which has the following characteristics: NMR (CDCl ₃ ) 99 (3, s), 104 (3, s), 277 (1, s, H-3), 344 (2, g-like singlet, azetidinone H) and 472 Hz (4, m, ArH).

B. Use of N ^ '- dicyclohexylcarbodiimide

A solution of 1.45 g (4 mmol) 6- (2'-carboxybenzamido) -penicillanic acid in 40 ml of methylene chloride is with 1.0 g (4 mmol)) Ν, Ν'-dicyclohexylcarbodiimide offset. The whole is left at room temperature for 0.5 hours, after which the reaction mixture is filtered

409881/1243

- 5Γ-

and the filtrate is evaporated to dryness in vacuo. The NMR spectrum shows a 3: 1 mixture of phthalisoimide and phthalimide .

Example 28 p-Methoxybenzyl-6- (2 '"carboxybenzamido) penicillinate

A solution of p-methoxybenzyl-6-phthalimidopenicillinate (2.33 g, 5 mmol) in 50 ml of tetrahydrofuran is mixed at 0 ° C. with 1.35 g (about 5.5 mmol) of Na ₂ S.9H ₂ O and 50 ml Ice water added. The whole is left at 0 ° C. for 12 minutes, after which 5 ml of 1.0 η hydrochloric acid are added and the mixture is concentrated in vacuo to a volume of about 50 ml. The mixture obtained is washed twice with 50 ml of ethyl acetate each time. The pH of the aqueous layer is then adjusted to 4.1 with concentrated hydrochloric acid and then extracted with 35 ml of ethyl acetate. The ethyl acetate extract is washed with brine and dried over magnesium sulfate. Evaporation in vacuo gives 2.35 g of p-methoxybenzyl 6- (2'-carboxybenzamido) penicillinate in the form of a colorless foam, which has the following characteristics: NMR (CDCl ₃ ) 82 (3, s), 92 ( 3, s), 227 (3, s, OMe), 263 (1, s, H-3), 305 (2, s, CH ₃ ), 330 (2, m, β-lactam H), 400-480 (8, m, ArH) and 630 Hz (1, broad s, COOH).

Example 29

p-methoxybenzyl-e-phthalisoimidopenlcillinate

Ethyl chloroformate (0.2 ml, 2 mmol) is added to a solution of p-methoxybenzyl-6- (2 ¹ -carboxybenzamido) penicillinate (968 mg, 2 mmol) and triethylamine (0.27 ml, 2 mmol) in 15 ml of tetrahydrofuran given at 0 ⁰ C. You hold the whole thing for 5 minutes

/ »09881/1243

at OC, whereupon the mixture is allowed to warm to room temperature, then filtered and finally evaporated to dryness in vacuo. The crude product is taken up in 20 ml of ethyl acetate, whereupon it is washed in sequence with 10 percent sodium bicarbonate, water and brine. After drying over magnesium sulfate, the ethyl acetate solution is evaporated to dryness in vacuo. This gives a light yellow foam of p-methoxybenzyl-6-phthalisoimidopenicillinate, which has the following characteristics: NMR (CDCl ₃ ) 84 (3, s), 98 (3, s), 23, 230 (3, s, OMe) , 271 (1, s, 3-H), 309 (2, s, CH ₂ ), 338 (2, q, J = 4.0 Hz, azetidinone H), 410-490 Hz (8, m, ArH) .

Example 30 p-Methoxybenzyl-S-aminopenicillinate

A solution of 480 mg (1 mmol) of p-methoxybenzyl-6-phthalisoimidopenicillinat in 35 ml of dry tetrahydrofuran is added at -76 ⁰ C with a solution of O, O53 ml (1 mmol) of methylhydrazine in 5 ml of tetrahydrofuran. The solution is then removed from the dry ice-acetone bath and allowed to warm to room temperature over a period of 1 hour. The reaction mixture is evaporated to dryness in vacuo and the residue obtained is taken up in 15 ml of chloroform. The mixture is allowed to stand for 1 hour at room temperature, and during this time falls Methylphthalhydrazid (m.p. 243-245 ⁰ C). By filtering off and evaporating the filtrate in vacuo, a light yellow foam is obtained, which is taken up in 20 ml of ethyl acetate, whereupon it is extracted twice with 10 ml of 0.05 η hydrochloric acid. The aqueous acidic extracts are combined and added dropwise to a stirred slurry of 25 ml of ethyl acetate and 25 ml of 10 percent sodium bicarbonate solution. The organic layer is separated, washed with brine and dried over magnesium

4098 8-1 / 1243

sulfate dried. Evaporation in vacuo gives 200 mg (60%) p-methoxybenzy1-6-aminopenicillinate in the form of a colorless foam, which has the following characteristics: NMR (CDCl ₃ ) 85 (3, s), 97 (3, s), 231 (3, s, OCH ₃ ), 266 (1, s, H-3), 274 (1, d, J = 4.0 Hz, azetidinone H), 311 (2, s, CH ₃ ), 332 ( 1, d, J = 4.0 Hz, azetidinone H), and 410-450 Hz (4, m, ArH); Mass spectrum m / c 336, M.

409881/1243

Claims (1)

Claims 1. Process for splitting the araidic acid function of a Compound of formula 0 Il R-C I COOH ( COORi where R and R are hydrogen or where R and R 3 tbsp together with the carbon atoms to which they are attached represent an ortho-phenylene ring, the substituent Z for or stands, R ₁ denotes hydrogen or a carboxy protective group and R _{2 represents} hydrogen, acetoxy, methoxy, methylthio, (5-methyl-1,3,4-thiadiazol-2-yl) thio or (1-methyl-1H-tetrazol-5-yl) -thio, characterized in that one (1) from the above compound to form the corresponding one Imids of the formula 409881/1243 RRII ^a CC / Λ O = C C = N, 0 ' ■ Ν II COORi Splits off water, (2) the imide thus obtained with a hydrazine of the formula R ₃ HNNHR ₄ , where R_ and R- independently of one another represent hydrogen or methyl stand, converts, lind (3) a) the reaction mixture of this hydrazine treatment with formation of the corresponding 7-acylamidocephalosporin or 6-acylamidopenicillin reacts with an acyl halide, or b) if at least one of the substituents R ₃ and stands for methyl, the corresponding 7-aminocephalosporin or from the reaction mixture of the abovementioned hydrazine treatment 6-aminopenicillin wins, or c) if the substituents R- and jk R _-, hydrogen, heating the reaction mixture of the above hydrazine treatment to a temperature of about 5O ⁰ C to about 100 ⁰ C, to yield the corresponding 7-amino cephalosporin or 6-aminopenicillin or 409881/1243 d) if the substituents R 1 and R _{4 are} hydrogen, the reaction mixture obtained from the above hydrazine treatment is reacted with an acid, resulting in acid addition salts of the corresponding 7-aminocephalosporin or 6-aminopenicillin. 2. The method according to claim 1, characterized in that one carries out the elimination of water from the Amidsäureverbindung by treatment with N _f N'-dicyclohexylcarbodiimide in an inert solvent at temperatures between about 0 ⁰ C and about 30 ⁰ C. 3. The method according to claim 1, characterized in that the elimination of water from the amic acid compound by treatment with trifluoroacetic anhydride in the presence of a tertiary amine at temperatures between about 0 C and about 30 ⁰ C undertakes. 4. The method according to claim 1, characterized in that from the amic acid compound in which R _{1 stands} for a carboxy protective group, water is split off by treatment with alkyl chloroformate in the presence of a tertiary amine at temperatures between about -20 ⁰ C and +5 ⁰ C and subsequent warming to room temperature. 5. The method of claim 1 to 4, characterized in that the first stand isoimide with up to one equivalent of a hydrazine, wherein R and R ₄ is hydrogen, per equivalent of the isoimide, at a temperature between about -76 ⁰ C. and reacting at about room temperature for a period of about one to about 10 minutes, and that 409881/1243 then obtained reaction mixture with about 1 to about 2 equivalents an acid from the group consisting of hydrochloric acid and hydrogen bromide acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid or sulfuric acid per "equivalent of the original isoimide for about 5 to about 10 minutes for reaction brings, whereby one obtains an acid addition salt of the corresponding Aminocephalosporins or AminopeniciHins. 6. The method according to claim 1 to 4, characterized in that the isoimide is first treated with up to one equivalent of a hydrazine in which at least one of the substituents R ₃ and R _{4 is} methyl, per equivalent of the isoimide at a temperature of -76 ⁰ C to about room temperature over a period of about 1 to 10 minutes, whereby one arrives at the corresponding aminocephalosporin or aminopenici11in. 7. The method according to claim 1 to 6, characterized in that that the amic acid function of a compound of the formula I in which the substituents R and R are hydrogen, splits. 8. The method according to claim 1 to 6, characterized in that the amic acid function of a compound of formula I in which the substituents R and R _a together with the carbons atoms to which they are bound, an ortho-phenylene ring mean splits. 9. The method according to claim 1 to 8, characterized in that the amic acid function of a compound of formula I in which the substituent Z is 409881/1243 CH ₃ stands, splits. 10. The method according to claim 1 to 8, characterized in that the amic acid function of a compound of the formula I, in the case of the substituent Z for stands, splits. 11. Compound of Formula R Ra I I C = C COORi where R and R, are hydrogen or where R and R, a a along with the carbon atoms to which they are attached, mean an ortho-phenylene ring. 409881/1243 the substituent Z for or
-CH ₂ R ₂ stands, R ₁ denotes hydrogen or a carboxy protecting group, and R _{2 represents} hydrogen, acetoxy, methoxy, methylthio, (5-methyl-1,3,4-thiadiazol-2-yl) thio or (1-methyl-1-H-tetrazol-5-yl) -thio. 12. A compound according to claim 1, characterized in that R and R are hydrogen. 13. A compound according to claim 11, characterized in that that the substituents R and R together with the carbon atoms, to which they are bound represent an ortho-phenylene ring. 14. A compound according to claim 11 to 13, characterized in that the substituent R- is C - C ^ -alkyl, 2,2,2-trichloroethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, C ₂ -Cg -Alkanoyloxymethyl, phenacyl or p-halophenacyl. 15. A compound according to claim 11 to 13, characterized in / that the substituent R _{1 is} hydrogen. 409881/1243 16. A compound according to claim 11 to 14, characterized in that that the substituent R- is p-nitrobenzyl. 17. A compound according to claim 11 to 16, characterized in that that the substituent Z is the group CH ₃ means. • 18th Connection according to claim 11 to 13, characterized in that that the substituent Z is the group ! -CH ₂ R ₂ means. 19. A compound according to claim 18, characterized in that the substituents R ₁ . and R _{2 is} hydrogen 20. A compound according to claim 18, characterized in that R _{1 is} p-nitrobenzyl and R _{2 is} hydrogen. 21. A compound according to claim 18, characterized in that R. is hydrogen and R _{2 is} acetoxy. 409881/1243 22. A compound according to claim 18, characterized in that the substituent R _{1 is} p-nitrobenzyl and R _{2 is}
Acetoxy stands. 23. A compound according to claim 18, characterized in that the substituent R- is hydrogen and the substituent R _{2 is} (5-methyl-1,3,4-thiadiazol-2-yl) thio. 24. A compound according to claim 18, characterized in that R _{1 is} p-nitrobenzyl and R _{2 is} (5 ~ methyl-1,3,4-thiadiazol-2-yl) thio. 25. A compound according to claim 18, characterized in that R _{1 is} hydrogen and R _{2 is} (1-methyl-IH-tetrazol-5-yl) thio. 26. A compound according to claim 18, characterized in that R _{1 is} p-nitrobehzyl and R _{2 is} (1-methyl-1H-tetrazol · 5-yl) thio. 27. Process for the preparation of an isoimide of the formula R. Ra \ i ι C. ι / = C -> COOR1 409881/1243 ~ 66 - where R and R are hydrogen or where R and R a a along with the carbon atoms to which they are attached, mean an ortho-phenylene ring, the substituent Z for rCH-, or - ^CH 2 ^R 2 stands, R- denotes hydrogen or a carboxy protective group and R _{2 represents} hydrogen, acetoxy, methoxy, methylthlo, (5-methyl-1,3,4-thiadiazol-2-yl) thio or (1-methyl-iH-tetrazol-5-yl) -thio, characterized in that that nan from an amic acid of the formula Il R -C-C-NH, 3 ■■ R-C I COOH 0 ' COORi wherein R, R, R- and Z have the above meanings. Splits off water. 28. The method according to claim 27, characterized in that the amic acid with N, N-dicyclohexylcarbodiimide converts ¹ in an inert solvent at temperatures between about 0 ° C and about 3O ⁰ C.. 409881/1243 29. The method according to claim 27, characterized in that with Trifluoressgisäureanhydrir in the presence reacting the amic acid of a tertiary amine at temperatures between about 0 C and about 30 ⁰ C. 30. The method according to claim 27, characterized in that the amic acid, in which the substituent R _{1 stands} for a carboxy protective group, is treated with an alkyl chloroformate in the presence of a tertiary amine at temperatures between about -20 ⁰ C and about +5 ⁰ C, after which it is warmed to room temperature. 31. The method according to claim 27 to 30, characterized in that an isoimide of the formula II is prepared in which the substituents tuenten R. and R stand for hydrogen, a 32. The method according to claim 27 to 30, characterized in that an isoimide of the formula II is prepared in which R and R along with the carbon atoms to which they are attached, mean an ortho-phenylene ring. 33. The method according to claim 27 to 32, characterized in that an isoimide of the formula II is prepared in which the substituent Z for CH., stands. 409881/1243 - 58 - 34. The method according to claim 27 to 32, characterized in that an isoimide of the formula II is prepared in which the substituent Z for stands. 35. Process for cleaving the isoimido function of an isoimide compound of the formula R Ra 1 I. C = C _{0 = c} C = N, 0 ' II COORi where R and R are hydrogen or where R and R el α, together with the carbon atoms to which they are attached represent an ortho-phenylene ring, the substituent Z for -CH ₉ R ₉ ⁰ ^ ' ^ ^CH 3 stands, R ₁ denotes hydrogen or a carboxy protective group and R _{2 represents} hydrogen, acetoxy, methoxy, methylthio, (5-methyl-1,3,4-thiadiazol-2-yl) thio or (1-methyl-iH-tetrazol-5-yl) thio 409881/1243 stands, characterized in that one (1) the above isoimide compound with a hydrazine of the formula R ₃ HNNHR ₄ wherein R ₃ and R ₄ independently of one another are hydrogen or methyl, reacts and (2) a) the reaction mixture for this hydrazine treatment Preparation of the corresponding 7-acylamidocephalosporin or 6-acylamidopenicillin treated with an acyl halide, or b) if at least one of the substituents R 1 and R _{4 is} methyl, the corresponding 7-amincephalosporin or 6-aminopenicillin is obtained from the reaction mixture from the above hydrazine treatment, or c) where the substituents R ₃ and R ₄ is hydrogen, the reaction mixture of the above hydrazine to a temperature between about 50 ^0C and about 100 ^0C heated, thereby obtaining the corresponding 7-amino cephalosporin or 6-aminopenicillin or d) if the substituents R ₃ and R _{4 are} hydrogen, the reaction mixture from the above hydrazine treatment is reacted with an acid, whereby an acid addition salt of the corresponding 7-aminocephalosporin or 6-aminopenicillin is obtained 36. The method according to claim 35, characterized in that the isoimide is first with up to one equivalent of a hydrazine in which R ₃ and R _{4 are} hydrogen, per 409881/1243 Equivalent of the isoimide, at temperatures between about -76 C and about room temperature for a period of about 1 minute to about 10 minutes, whereupon one the reaction mixture obtained with about 1 to about 2 equivalents of an acid from the group consisting of hydrochloric acid, Hydrobromic acid, phosphoric acid, p-toluenesulfonic acid, Methanesulfonic acid "or sulfuric acid per equivalent of the original isoimide for a period of reacted for about 5 to about 10 minutes, thereby forming an acid addition salt of the corresponding aminocephalosporin or receiving aminopenicillins. 37. The method according to claim 35, characterized in that the isoimide is first mixed with up to one equivalent of a hydrazine in which at least one of the substituents R ^ and R is methyl, per equivalent of the isoimide at a temperature of about - treated 76 ⁰ C to about room temperature over eIHE period of about 1 to about 10 minutes, so as to obtain the corresponding amino cephalosporin or aminopenicillin. 38. The method according to claim 35 to 37, characterized in that the isoimido function of a compound of Formula II cleaves, in which the substituents R and R for Stand for hydrogen. 39. The method according to claim 35 to 37, characterized in that the isoimido function of a compound of Formula II splits, in which the substituents R and R to- together with the carbon atoms to which they are attached, stand for an ortho-phenylene ring. 409881/124 3 40. The method according to claim 35 to 39, characterized in that that one cleaves the isoimido function of a compound of formula II in which the substituent Z is for stands. 41. The method according to claim 35 to 39, characterized in that that one cleaves the isoimido function of a compound of formula II in which the substituent Z is for stands. 409881/1243